DE2540522A1 - DIAZEPINE DERIVATIVES - Google Patents

Description

\ t Sep 1

RAN 4008/284

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland Dia ζ epin derivatives

The present invention relates to pharmacological active imidazο [1,5-a] [1,4] diazepine compounds. The chemical The structure of these compounds can be represented by the following formula will:

where A is the group -O = E , IL is hydrogen,

lower alkyl, lower hydroxyalkyl, lower acyloxyaXkyl, Phenyl, lower alkoxyalkyl, lower haloalkyl,

809815/1301

254Q522

lower aminoalkyl, substituted lower aminoalkyl, substituted phenyl, pyridyl, Aralkyl or the groups ROO or RO'OC- (in which R is hydrogen or lower alkyl) means, Rp is hydrogen, lower alkyl, lower hydroxyalkyl, lower acyloxyalkyl, lower alkoxyalkyl, lower alkenyl, lower haloalkyl, lower aminoalkyl, amino, cyano, lower Oyanoalkyl, substituted amino, substituted lower aminoalkyl, the group ROOO- (where R Is hydrogen or lower alkyl), the group ROO (where R is hydrogen or lower alkyl), or derivatives thereof, i.e. the group R-O = IT-R ' (where R 'is hydrogen, lower alkyl, hydroxy, phenyl, alkoxy, amino, mono- or dialkylamino or arylamino and R is hydrogen or lower

R ' ^{lf are} alkyl), the group -CON ^ (where R "

R "and R ¹ " are each hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl or aryl, or R "and R"'together form part of a heterocyclic ring or the group (OHp) _n HR R (where R and -R are hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl or aryl

IV V

or R and R together form part of a heterocyclic ring) or the group E ¹⁰

₁₉ (where R, R ^ and ΈΓ * hydrogen,

Xl "I * ZT A

lower alkyl or the group (OEL) ₀ HR R where η 1 to 4 and R and R are hydrogen or lower alkyl or R and R together form part of a heterocyclic ring), R_ and R ₁ - hydrogen, lower alkyl, lower Alkanoyloxy, hydroxy or lower alkoxycarbonyl mean

B0981S / 1301

where for the case that one of R, and R ₁ . Is alkanoyloxy, hydroxy or lower alkoxycarbonyl, the other is hydrogen or lower alkyl, R. is hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, Rg is phenyl, mono-substituted Phenyl, di-substituted phenyl, pyridyl or mono-substituted

tes pyridyl means and

one of the groups

and

means, where X is chlorine, bromine or iodine and T is hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof.

Various analogous compounds derived from the above compounds as well as various ones new intermediates leading to the above compounds are also encompassed by the present invention and are themselves pharmacologically active or valuable intermediates to pharmacologically active compounds.

Analogs of the above compounds encompassed by the present invention include compounds the formula

80981S / 13Q1

2540 * 22

IA.

worm

in A the group -Ο-Ή is, E-, Ε «, (2 |

^E 6

and R, - the meaning given in formula I.

and R ₁ - hydrogen or lower O

Means alkyl, and pharmaceutically acceptable salts thereof.

Other new analogs include compounds of the formula

IB

where A is one of the groupings

-N

H
C-

.Ν

and

C = N

means, R-, R ₂ , Rg and (z | l have the meaning given in formula I, R "hydrogen,

80981S / 1301

is lower alkyl, lower alkenyl, lower alkynyl, acyl, hydroxy, nitroso, an aromatic or aliphatic sulfonyl group or lower alkoxycarbonyl, R- and Ej- are hydrogen or lower alkyl and V is hydrogen or lower alkyl,
and pharmaceutically acceptable salts thereof.

As used in the present specification, the term "lower alkyl" or "alkyl" means straight chain or branched hydrocarbon radicals with 1-7, preferably 1-4 .carbon atoms, such as methyl, ethyl, propyl, isopropyl, Butyl and the like.

With the term "lower alkanoyl" or "acyl" as used herein, the acyl radical of an alkanecarboxylic acid is used by 1-7 »preferably 1-4 carbon atoms, for example acetyl, propionyl, butyryl and the like, i.e.

20 20

Radicals of the formula R -G-, in which R is hydrogen or alkyl

0
Means 1-6 carbon atoms. The term “lower alkanoyl” also includes a protected ketone, such as an acetal or a ketal having 2 to 7 carbon atoms, for example a group of the formula

20th
wherein R is hydrogen or alkyl having 1-6 carbon atoms. The ketal or aldehyde protecting group is used to prevent conversion of the ketone or aldehyde contained therein

609815/1301

20th
(R ~ $ ~) ⁱⁿ oxidation, reduction and condensation reactions

to avoid.

The term "halogen" includes all four forms thereof, i.e. chlorine, bromine, fluorine and iodine.

"Aromatic and aliphatic sulfonyl groups" are to be understood as meaning radicals of the formula SOpX ', where X ^{f is} a branched or straight-chain aliphatic group with 1-7, preferably 1-4 carbon atoms (such as methyl) or a substituted or unsubstituted aromatic group (such as phenyl or substituted phenyl, for example ToIyI) means.

The phenyl radical denoted by R ^ can be mono- or be di-substituted, provided that the position 2 and 3 »2 and 5 or preferably 2 and 6 des Phenyl radicals are occupied. Suitable mono-substituents include halogen and nitro, preferably in the 2-position of the phenyl radical. Suitable di-substituents are 2,6- or 2,5-di-halo and 2,6- or 2,5-halo-nitro. In case of Mono-substituted pyridyl includes suitable substituents Halogen and nitro.

In the case of different substituents R ₁₂ and Rr, optical isomerism results and such optical antipodes and racemates are encompassed by the present invention.

The term "aryl" denotes a substituted or unsubstituted monocyclic aromatic radical, such as Phenyl, chlorophenyl, tolyl and the like. If in this Description states that certain residues form part of a heterocyclic ring, it is meant by that these residues, together with the nitrogen atom, on which

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they sit, form a preferably 5- to 6-membered ring ", which contains at most one further heteroatom, this heteroatom preferably being nitrogen or oxygen. With the questionable heterocyclic ring are thus residues such as morpholino, Piperazino, piperidino and pyrrolidino meant.

The term "alkoxy" means straight-chain or branched saturated hydrocarbonoxy groups with 1 "to 7, preferably 1-4 carbon atoms meant, such as methoxy, ethoxy, propoxy and the like.

The term "lower alkenyl" as used herein means straight or branched chain containing an olefinic double bond Hydrocarbon groups of 2 to 10, preferably 2 to 6 carbon atoms are meant, i.e. radicals of compounds of the formula C Ξ «where m2 is to 10, for example allyl.

As used herein, the term "substituted amino" means a -iffiL-G group which is replaced by lower alkyl or aryl (such as phenyl or tolyl) can be mono- or di-substituted (For example, methylamine or dimethylamino) or a Acylamino group, such as acetamino, which is additionally represented on the nitrogen atom by lower alkyl or aryl (such as methyl, Phenyl or tolyl) can be substituted.

By the term "aralkyl" is meant a hydrocarbon group which has aromatic and aliphatic structural parts contains, i.e. a hydrocarbon group in which a hydrogen atom of a lower alkyl group is replaced with a monocyclic aryl group (such as phenyl, tolyl and the like) is.

In all of the compounds designated by the above formulas, those are preferred in which R-, hydrogen or means lower alkyl (preferably methyl), R, and R, -

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Are hydrogen,

is, where R.

preferably in the 8-position of the imidazobenzodiazepine structure and is hydrogen, nitro or halogen ('preferably chlorine), A is the group -C = H, where Rg is phenyl

or substituted by halogen, Uitrο or lower alkyl Phenyl means, preferably halophenyl, especially fluorophenyl, where the fluorine atom is preferably in the 2-position, and Rp is hydrogen, lower alkyl, lower hydroxyalkyl (such as hydroxymethyl), a carboxylic acid hydrazide group (i.e. a group of the formula -COHHEHp), or a carboxamido group (i.e. a group of the formula -COHHp), for example compounds of the formula

where R '., and R'p as in the following Formula IC are defined.

As is clear from the foregoing, encompasses a particularly preferred group within the scope of the present invention Compounds of the formula

60981S / 13Ö1

ic

where R 'is hydrogen or lower alkyl (preferably methyl), R. is hydrogen, M.trο or halogen (preferably chlorine) "and in a particularly preferred embodiment is in the 8-position of the imidazobenzodiazepine structure, Rg _{0 is} phenyl or halogen , Fitro or lower alkyl substituted phenyl (preferably halophenyl, especially fluorophenyl, where the fluorine atom is preferably in the 2-position of the phenyl radical), R ₂ 'denotes hydrogen, lower alkyl, lower hydroxyalkyl (such as hydroxymethyl) a carboxylic acid hydrazide group (such as -COHEHHp) or means a carboxamido group (ie -COMH ₂ ).

Another preferred class of compounds within the scope of Formula I are those wherein R ', R'p> & * »R., Rg and A are those given in formula IC Have meaning and R, - is lower alkyl (preferably methyl), for example compounds of the formula

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ID

Compounds of the formula ID and their pharmaceutically acceptable salts exhibit optical isomerism. Such a compound of the formula ID, wherein R_ is hydrogen and R ^ is methyl, has been separated into its optical enantiomers by a method similar to that described in Advanced Organic Chemistry, L. Fieser and M. Fieser, 1961, pages 85-86, Reinholt Publishing Co. will generally be discussed. Both the optical isomers and the racemic form of Compound ID show pharmacological activity. In the case of the tartrates of compounds of the formula ID, the (+) - isomer is considerably more active than the (-) - isomer. The less active (-) - isomer can, if necessary, be converted into its active racemic form, for example by treatment with a non-aqueous base such as sodium tert-butoxide in the presence of an organic solvent in which the isomer is soluble .

The term "pharmaceutically acceptable salts" includes salts with inorganic and organic, pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Such salts can be used in view of the prior art and "taking into account the nature of the compound to be converted into a salt

609816/1301

can be readily produced by any person skilled in the art.

The most preferred pharmaceutically acceptable acid addition salts of compounds of the formulas IC and ID are:

-O- (2-fluorophenyl) -l-methyl ^ H-imidazo [1,5-a] [1,4] benzodiazepine maleate;

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo- [1,5-a] [1,4] benzodiazepine maleate.

Also encompassed by the present invention are compounds obtained by ring opening compounds of

• Formula I, in which ■ ν? 'I denotes R.-phenyl. Such Compounds have the formula

IE

^R 6

where Y ~ is the anion of an organic or inorganic acid, R ₁ S Rc>& * v ^ R ¹ ? ^{as ol3en are defined in} formulas IC and ID and R. and R ^ those in formula I

4 6

have given meaning.

It has been found that certain compounds of the formula I in solution give rise to corresponding compounds of the formula IE to open. Such open compounds exist in solution in a pH-dependent equilibrium with compounds of the formula I, i.e. the corresponding connections with closed ring.

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The compounds of the formula IE can be isolated as acid addition salts by using the corresponding compounds closed ring treated with an aqueous mineral acid and then the solvent evaporated. In isolated form these salts develop a pharmacological activity, which is comparable to that of the corresponding closed ring compounds.

The imidazo [l, 5-a] [1,4] diazepines of the formula I, their Analogs of the formulas IA and IB and the pharmaceutically usable acid addition salts of these compounds can according to the invention are produced according to the various process aspects which are defined further below in claim 1.

Compounds of the formula IB in which A is -G = NTt,

^R 6

is obtained by converting compounds of the formula I. into their N-oxides. This conversion takes place by oxidation a compound of formula I with an organic peracid. To carry out this reaction, a common organic Peracid can be used, such as peracetic acid, perpropionic acid, m-chloroperbenzoic acid and the like. The oxidation can be at room temperature or above or below it be performed.

Compounds of the formula ΓΒ in which A is -C = N ^,

I ο

^R 6

can then be used to prepare compounds of the formula I in which R _{1 or R 1 is} alkanoyloxy or hydroxy by methods known per se, for example by a Polonovski rearrangement with an acid anhydride to form the alkanoyloxy radical, which is then treated with an alkali metal hydroxide (such as sodium hydroxide) can be converted into the hydroxyl group. An example of such a polohovski-

6 0 9 8 1 S / 1 3 0 1

Rearrangement is described in U.S. Patent Mo. 3,296,249.

HI s

Compounds of the formula IB, in which A is -C-Mr ^,

R ₆ R ₇

is obtained by reducing compounds of the formula I to compounds of the formula

IB ¹

where R- ,, R ₂ , R-, fe Jl and R ₁ - have the meaning given in formula I, R. has the meaning given in formula I, but is not Miter, and Rg has the meaning given in formula I. , however, not mitrophenyl (because nitro groups can be reduced to amino groups under the reaction conditions).

These compounds can then be converted into other compounds of the formula IB.

Any suitable reducing agent can be used to reduce the compounds of the formula I to compounds of the formula IB ' use, but preferably hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of Acetic acid. These compounds of the formula IB 'can be converted into compounds of the formula IB ', where R "has a meaning other than Has hydrogen, can be converted, for example, with a lower alkyl halide (e.g. Methy! Iodid) a lower alkenyl halide (e.g. allyl bromide), a lower

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Alkynyl halide (for example propargyl bromide) an alkyl or arylsulfonyl halide (for example tosyl chloride, mesyl chloride), nitrosyl chloride or an agent which provides a lower alkanoyl group (for example acetyl chloride). The term "lower alkynyl" used above includes unsaturated straight-chain and branched hydrocarbon radicals which contain triple bonds, ie radicals of compounds of the formula CX, ", where n is ¹ is 3-7, for example propargyl.

This aspect of the process is expediently carried out in the presence of an inert organic material Solvent, for example an alkanol (such as ethanol and methanol), an ether (such as diethyl ether and tetrahydrofuran) of dimethylformamide and the like. Appropriately, an acid acceptor is brought into the reaction zone, when using a halide such as an arylsulfonyl halide (such as Tosy! halide) or an alkylsulfonyl halide (such as Me sy! halide) formed hydrogen halide to tie. Suitable acid acceptors are tertiary amines, for example triethylamine, pyridine and the like.

Temperature and pressure are not critical factors for the first stage of the process for lifting compounds of the formula I in the corresponding compound of the formula IB. The compounds of the formula IB 'are, however, preferably prepared at about room temperature and atmospheric pressure, and the compounds of the formula IB ^{1 are converted} to compounds of the formula IB with a radical R 1 other than hydrogen at room temperature or above.

Reduction of compounds of the formula ΓΒ, in which A

-C = N ^ T, with hydrogen in the presence of a platinum catalyst

R °
and acetic acid leads to compounds of formula IB, wherein A

609815/13 01

I ^

and R _{7 is} hydroxy.

.H

I /

Compounds of the formula IB, wherein A is -C-H; is

and R _{7 is} hydroxy can be converted into the corresponding unsaturated imine of the formula I by treatment with a mixture of isetic anhydride and pyridine. No other solvent is necessary for this reaction and temperature is not critical, although the reaction is best carried out at room temperature.

■ Compounds of the formula IB in which R _{7 is} acetyl, mesyl or tosyl can be converted into the corresponding unsaturated imines of the formula I by treating them with a non-aqueous base, for example with potassium tert-butoxide in the presence of an inert solvent such as tetrahydrofuran, dimethylformamide and the like. Such a reaction and the conditions under which it is carried out are known per se, see US patent ITo. 3 625 957.

Compounds of the formula IB in which R _{7 is} hydrogen can be converted into the corresponding unsaturated compounds of the formula I by oxidizing the secondary amino group in the 5-position. Such a selective oxidation can be carried out with known oxidizing agents and by known methods, see US Pat. 3,322,753.

The conversion of compounds which are in the 5,6-position See the element of a Schiff base and in which R. mean amino, to compounds in which R. mean nitro ' expediently e.g. by a Sandmeyer reaction in which the amino group is replaced by a nitro group, be accomplished; one treats, for example, a

809815/1301

■ bond of the formula I, in which IL, IU, A and Rg have the meaning given in! Formula I and R, and R ₁ - are hydrogen or lower alkyl, with an excess of sodium nitrite in the presence of a mixture of copper sulfate and sodium sulfite, where dilute sulfuric acid is used as the solvent.

The resulting intermediate of the formula

W * ²

Ij XXIII '

Vf 'J

where R ₁ , R _? and R, - have the meaning given in formula I,

can then be converted into a corresponding compound of formula I. The above process can be carried out in a two-step sequence without isolation of the intermediate of the following formula XXIV, by the compound of the above formula XXIII 'with phosphorus tribromide ■ in an inert organic solvent, for example dichloromethane, and at a temperature of about -10 ° to 25 ⁰ C (although the temperature is not critical), followed by a treatment in situ with ammonia, preferably liquid ammonia, which is allowed to warm to room temperature.

It has been shown that the above Sandmeyer reaction can also be used for the preparation of compounds corresponding to those of the formula XXIII ¹ which have a cyano, chlorine, bromine or hydroxyl group instead of the nitro group.

809815/1301

Such corresponding compounds can be ring-closed in a manner analogous to those of the formula XXIII ' Analogs are transferred.

It is clear to those skilled in the art that in the course of the above reactions certain other substituents also can be attacked, for example if R, or Rp contain primary amino groups, alcohol groups, carboxylic acid groups or carboxylic acid ester groups, etc., but such Vulnerable groups can be modified before carrying out the above reaction sequence or by a suitable one Protection group are blocked. Methods for modifying or protecting vulnerable groups are well known .

Compounds of the formula IB, in which A -C-

means can be obtained by reacting a compound of the formula I directly with ethylene oxide or propylene oxide in The presence of a Lewis acid or by making a compound the formula

^ CH ₂ OH ^ ¹¹¹¹

TT

wherein R ₁ , R ₂ , \ Z \\ and Rg have the meaning given in formula I, reacted with phosphorus tribromide, followed by treatment of the intermediate (XXIV) with ethanolamine, a. 1-alkylethanolamine or a 2-alkylethanolamine, as shown in the following reaction scheme.

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/ V>

• XXIII

XXW NH

CH

Y is hydrogen or lower alkyl

The compounds of formula XXIII can be obtained by adding a compound of formula IE in the presence a suitable solvent, such as water or diluted Mineral acid, reacts with sodium nitrate. The reaction temperature can be between -10 ° and room temperature. The reaction of the compound of formula XXIII with phosphorus tribromide is carried out as outlined above, preferably in an inert organic solvent such as dichloromethane and at about room temperature, although such temperature is not critical.

The reaction of the compound of the formula XXIV with ethanolamine or a 1-alkyl- or 2-alkylethanolamine takes place in situ, i.e. in a suitable inert solvent such as dichloromethane and at a temperature between -10 ° and reflux temperature, preferably around room temperature .

The direct reaction of compounds of the formula I with ethylene oxide or propylene oxide is preferably carried out by a Lewis acid catalyzed, for example titanium tetrachloride, boron trifluoride, etc.

When in the compounds of formula I and their analogues

609815/1301

a ketal group, for example

as a substituent in the 8-position in an imidazobenzodiazepine is present, such an eetal group can be converted into an 8-position keto group by mild acidic hydrolysis will. The 8-ketone can then be converted into a. 8 permanent secondary or tertiary alcohol, which is racemic in nature. The reaction conditions for this, i.e. for the above 2 stages are described in U.S. Patent Ro. 3,846,410.

As mentioned above, compounds of the formula I can be used to form compounds directly with ethylene oxide or propylene oxide of the formula IB of the oxazolo type are implemented. The reaction parameters and conditions for such a reaction are known per se, see for example US patent Uo. 3 868 362.

The compounds of the above formula I, including the preferred imidazobenzodiazepines of the formulas IO and ID, can be prepared in a wide variety of synthetic routes , including the following novel process aspects which form part of the present invention.

In one of the above-mentioned new according to the invention Process aspects for the preparation of compounds of the formula I are nitrosated a compound of the formula

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NHCH.

II

where A -C = K "

or -O = N ',

ι °

6 "6

R "and Rj- denote hydrogen or lower alkyl and (ZM

and Rg have the same meaning as above, and are connected the formula

III

in which A, R ₃ , R ₅ and (z || have the meaning given in formula II.

Such a hydrochloric acid formation can occur with in situ nitrous acid. Reagents which can be used for this purpose include: 1. ATk-fl.1iTne-ha.Tlnitrite, such as sodium nitrite, in the presence of organic or inorganic acids, such as glacial acetic acid, and aqueous or non-aqueous solvents; 2. alkyl nitrites, such as methyl nitrite, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or for example Dimethylformamide; 3 · a solution of gaseous nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a urination reaction should

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around or below room temperature, i.e. in the range from about -20 ° to 25 °.

The Eitrosoalkylamino group in the 2-position, for example -CH ₃

wise -ΙΓ-ΝΌ represents a leaving group. Equivalent leaving groups, which can be used as substituents in the 2-position include G groups such as alkoxy, e.g. OCEL, Alkylthio, e.g. -SCIL, halogen, e.g. chlorine, cyano, i.e. -CN,

and phosphates, such as ff \\. Reactions

for the formation of alkoxy and alkylthio groups in the 2-position are well known see, for example, G-. A. Archer and ■ L. H Sternbach, Journal of Organic Chemistry, 29 «231 (1964) and US Patent ETo. 3 681 341.

Compounds of the formula III can then be condensed with a nitroalkane, and a new one is obtained Intermediate of the formula

VO,

wherein Rp is hydrogen or lower alkyl and A, R ", R., (z | and R ^ are given in formula II Have meaning.

The Eondensationsreaktion takes place with an Eitroalkane (R ₉ -CH ₉ -NO ₉ ), ie Fitromethane, Mtroethane etc., in the presence of a base, which is strong enough to generate the Nitroalkananion. Suitable bases include alkali metal or alkaline earth

609815/1301

metal alkoxides, e.g. potassium tert-butylate, amides, e.g. Lithium amide, or hydrides such as sodium hydride. The reaction preferably takes place in an inert solvent such as dimethylformamide, dimethyl sulfoxide or ether, e.g. Tetrahydrofuran, "at temperatures below) or above room temperature, i.e. in a range from -50 ° to 150 °, preferably around room temperature.

The new compounds of the formula IV and the following formula V are not only important intermediates in the synthesis of compounds of formula I, but also exert a dampening effect on the central Nervous system.

Compounds of the formula IV can then be catalytically hydrogenated, e.g. via Raney nickel, or with other reducing agents, such as lithium aluminum hydride (only if A is not an N-oxide) and a compound is obtained the formula

where A -C = N

is, R ~,

and R, - the in

Formula II have the meaning given and R has the meaning given in formula II

but is not nitro and is substituted and means alkyl.

not through nitro

Hydrogen or lower

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The above exclusion of nitro from the substituent groups present results from the conversion of nitro in amino under the reaction conditions used in Stage IV-> V.

Solvents that are suitable for hydrogenation with Raney nickel include alcohols, e.g. ethanol, Ethers, e.g. tetrahydrofuran, diethyl ether, etc., hydrocarbons, e.g., toluene, and dimethylformamide. The reaction temperature can be above or below room temperature, i.e. -50 ° to 150 °, and the reaction can be with or without pressure, i.e. at atmospheric pressure or above.

Solvents which are useful in the use of a reducing agent such as lithium aluminum hydride include Ethers, e.g. tetrahydrofuran, dioxane, diethyl ether, and mixtures of ethers and hydrocarbons, e.g. tetrahydrofuran and benzene. The reaction can take place in a temperature range from below room temperature to reflux temperature, i.e. preferably in a range from -50 to 60 °.

The compounds of the formula V can then be acylated with an acylating agent, such as acid halides or acid anhydrides (ie compounds of the FmIeICR ₁ CO) PO in which R, which has the meaning given in formula I), for example with acetic anhydride or acetyl chloride, and a compound is obtained the formula

VI

e0981B / 1301

where A,

R ~

, R ₁ - those in formula Y

Have the meaning given, R- in the formula I has the specified meaning and T is hydrogen or -COR-. means.

The acylation of the compounds of the formula V to compounds of the formula VI can result in a mixture, consisting of the predominantly monoacylated product, i.e. in which the KEL group of V (position 2) in HHGOR-, is converted, and the diacylated product in which both the KELp-G group of V (2-position) and the nitrogen are acylated in 1-position. The yield of diacylated Product can be increased by subjecting the compounds of formula V to more rigorous conditions, i.e. excess of acylating agents and extended reaction time.

The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. water, Methylene chloride, benzene, chloroform, etc., and preferably using an acid acceptor such as organic or inorganic bases such as triethylamine, pyridine or alkali metal carbonates. The compounds of the formula VT can then form new compounds of the formula

VII

in which A, R ₁ , R ₂ , R ", (2 || and R, - have the meaning given in formula VI, are cyclized.

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The cyclization is done with a dehydrating agent carried out, e.g. Ph.osph.orpentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or inorganic acids, e.g. concentrated sulfuric acid. A Solvent is not required, but a solvent such as an aromatic hydrocarbon, e.g. Toluene or Xylene, can be used. The reaction takes place in a temperature range between about 100 ° to 200 °.

The compounds of formula V can also be used at room temperature or above, i.e. at 25 ° to 150 ° Acylating agents such as orthoesters, e.g. orthoacetic acid triethyiester, Orthoamids, e.g. ΙΤ, ΙΤ-dimethylformamide dimethylacetal, or a compound of the Pormel

^CH 3

^CH 3

CH-

optionally in the presence of an acid catalyst, for example an organic or inorganic acid, such as p-toluenesulfonic acid, Phosphoric acid etc. are reacted, the cyclization to compounds of formula VII taking place spontaneously. Other useful acylating agents include esters, e.g. Methyl acetate, amidines, e.g. acetamidine, ITitrile, e.g. Acetonitrile and ester imidates, for example a compound of the formula

CH- - C = HH

609815/1301

The compounds of the formula VII can then be converted into compounds of the formula

IC

wherein A, R ,, Rp, EL ·, ψη , and R ₁ - the in

Formula VI have the meaning given, are dehydrated.

Preferred reagents for dehydrogenation include manganese dioxide and palladium on carbon, although potassium permanganate can also be used. Solvents that can be used include chlorinated hydrocarbons, aromatic hydrocarbons, dimethylformamide etc. The dehydrogenation takes place at room temperature or above it, i.e. in a range of about 25 ° to 200 °.

The new compounds of the formula VII also have a dampening effect on the central nervous system and are part of this invention.

If desired, the above new method of run the intermediates of the formula IV or V to compounds of the formulas I and Iü without it being necessary to isolate intermediate products formed before proceeding to the next process step.

Compounds of the formula IA can be converted to the 4-5 position by isomerization of the 5,6 double bond in compounds of the formula I are formed. Compounds of formula IA can

609815/1301

by treating compounds of the formula I with an anhydrous Base are formed in the presence of an inert organic solvent '.

All that is required of the base is that they are is suitable for the purposes of the present invention, i.e. that it involves the conversion of a compound of formula I into the corresponding compound of formula IA. evokes. Among the numerous suitable bases, lower alkali metal alkoxides, such as sodium methylate, potassium tert-butylate and the like, and Alkali metal hydrides such as sodium hydride can be mentioned.

Representative, but by no means conclusive, examples of inert organic solvents which can be used for the purposes of the present invention are dimethylformamide, dimethyl sulfoxide, Tetrahydrofuran and the like. Again, temperature and pressure are not critical aspects of this conversion stage. However, it has been shown that temperatures between about -50 ° and about 80 °, preferably between about -30 and 25 °, are suitable.

It should be noted that in the acylation of compounds of the formula V to give the compounds of the formula VI, if R. is amino, this amino group can also be acylated to an acylamino group. The acylamino group can be converted back to the amino group by subjecting the compounds of the formula VII or I to mild hydrolysis.

. In the context of the present invention it was also found that compounds of the formula IV, V, VI and VII both may have optical as well as geometric isomerism.

Treatment of a compound of the formula V with acetic acid. And Zinc or any other suitable reducing agent, e.g. hydrogen in the presence of a catalyst (such as

609815/1301

Platinum) in dilute acetic acid solution, provides a compound of the formula

NH,

wherein A -C-I

is and

R ", R ₅ ,

and

have the meaning given in formula V.

Depending on the reduction method used above, Compounds of the formula VI in which Rp is hydrogen, as racemisch.es mixture of one or the other of the two possible Diastereomers are isolated.

By the direct reaction explained above, i.e. reaction of compounds of the formula V with acylating agents, such as Orthoesters, e.g. triethyl orthoacetate, in compliance with the above-mentioned reaction parameters for such a reaction a compound of the formula V can be converted into the dihydroimidazo derivative of the formula while maintaining the stereochemistry

VII '

609815/1301

in which A, R ₂ * R * and R ₁ - have the meaning given in formula V and R. is hydrogen or lower alkyl,
be transferred.

Compounds of the formula VII ¹ can also be prepared by reducing a compound of the formula VII, using reducing agents as mentioned above, for example acetic acid and zinc or hydrogen in the presence of a platinum catalyst in dilute acetic acid, and wherein the stereoisomer formed depends on the choice of reducing agent.

If desired, compounds of the formula VII ' are oxidized directly to analogous compounds of the formula I, using an oxidizing agent such as manganese dioxide in toluene or Benzene used. The reaction conditions to be used for this, as well as various oxidizing agents which can also be used are described in U.S. Patent No. 3,322,753.

609815/1301

Another process for the preparation of the new intermediates of the formula V, wherein R. and Rg are not Fit ro or Cyano are, consists in the reduction of compounds of the formula

where A

and

have the meaning given in formula II.

The reduction comprises the reaction of compounds of the formula X with a known reducing agent such as Raney-N-ickel in the presence of hydrogen or with other reducing agents such as lithium aluminum hydride. Solvents which are suitable for hydrogenation with Raney-Tickel include alcohols, e.g. B. ethanol, Aether, ζ. B. tetrahydrofuran, hydrocarbons, e.g. B. toluene, and dimethylformamide. The reaction temperature can be above or below room temperature (i.e. -50 0 to I50 G) and the reaction can take place with or without pressure, i.e. at one atmosphere or above it.

Solvents, which when using a reducing agent, such as aluminum aluminum hydride, include ethers, such as dioxane, diethyl ether and tetrahydrofuran. The reaction can

609815/1301

take place between below room temperature and reflux temperature, i.e. preferably in the range of -50 C to 60 C.

A variation on the above procedure is a mild one acid hydrolysis of the compounds of the formula X to give compounds of the formula

XI

wherein A, R., (5 Ij and Rg have the meaning given in formula X. own.'

The mild acidic hydrolysis is conveniently carried out with a dilute mineral acid, for example with aqueous sulfuric acid in aqueous alcohol. The reaction temperature can be between Room temperature, i.e. about 25 ° C, and temperatures above it, i.e. about 60 C. The compounds of formula XI can then reduced to the new intermediates of Formula V.

Another method, while not forming part of the present invention, is useful in preparing the new intermediates of formulas IV and V. The following procedure is off. Reasons for consistency in the present description

609815/1301

been taken.

The compounds of the above formula IV can be prepared be made by making a compound of the formula

XII

where A, ( «| j and R. have the above meaning,
with dimorpholinophosphinyl chloride to give a compound of the formula

XIII

where A, / β Ij and R. the meaning given in formula XII

. v-A.

owning

converts and then displaced the iminophosphate by the anion of a nitroalkane, the new intermediates of
formula

IV

609815/1301

- 53 -

where A,

own, receives.

and B .. the meaning given in formula XII

The displacement reaction takes place with a nitroalkane, i.e. Hitromethane, ETitroethane etc., in the presence of a base which is strong enough to form the nitroalkane anion. Suitable bases include the alkoxides, hydrides, amides or hydroxides of Alkali metals or alkaline earth metals. The reaction is preferably carried out in an inert solvent such as dimethylformamide, Dimethyl sulfoxide or an ether, at temperatures below or above room temperature, i.e. in the range from -50 C to 150 C.

Another process for preparing the intermediates of the formula IY, in which R ₁ - and R _{0 are} hydrogen, consists in the ring expansion of compounds of the formulas

-C ~ N

where AIV is and R ^ ₁

mel have given meaning.

R- and R. those in For-5 4

Ring expansion involves the reaction of the compounds of the formulas VIII or IX with nitromethane in the presence of a base, which is strong enough to form the hitromethane anion.

809815/1301

Suitable bases include the alkoxides of alkali metals and alkaline earth metals, e.g. B. Ealium tert-butoxide, amides, for example lithium amide, or hydrides, for example lithium hydride. The reaction can be carried out preferably in an inert solvent, such as anhydrous ether, for example tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc., and at temperatures in the range of about -20 ⁰ C to 25 ⁰ C.

Another process for the preparation of compounds of the formula I is shown in the following reaction scheme:

609815/1301

CH

^H. / -COOR

or isomer thereof

IiA ₉ UiCD (see next page)

609815/1301

-N- + H

-N-

OOR

COOR

NH

^ COOR

COOR

XVII A, B, C, D-

Unless otherwise stated, in the above reaction chema R denotes lower alkyl; R “and R, - have the meaning given in formula ID and R-. , A, R. and Rg have the meaning given in formula I.

1- «stage: Compounds of the formulas XIII or III can be condensed with the anion generated from the malonic ester to form compounds of the formula XIV. The anion is generated by deprotonating malonic esters with a suitable strong base, for example with alkoxides, hydrides or amides of alkali metals or earths

809815/1301

- 51 -

alkali metals. The reaction of the compounds of formula XIII or III with the malonic ester anion is preferably carried out in a solvent such as hydrocarbons, e.g. benzene, toluene, hexane, ethers, e.g. dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, etc. and at temperatures from below room temperature to 150.degree , preferably O ⁰ C to 100 G, room temperature being particularly preferred.

2nd stage: Compounds of the formula XV are obtained by decarboxylating compounds of the formula XIV by treating the compounds of the formula XIV with an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as alcohols, ethers or dimethyl sulfoxide, at temperatures between room temperature and reflux temperature, preferably 60 ⁰ C to 100 ⁰ C, treated.

3rd stage: Compounds of the formula XVI are obtained by kitrosation of compounds of the formula XV by treating the latter with nitrous acid, which is produced, for example, from an alkali metal nitrite, alkyl nitrite or mitrosyl chloride by reaction with an organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids, for example acetic acid, dimethylformamide, dimethyl sulfoxide and chlorinated hydrocarbons. The reaction can be carried out at about room temperature, although such temperature is not critical.

S09815 / 1301

4th stage: Compounds of the formula XVII are obtained by reducing compounds of the formula ZVI with Raney-Eickel and hydrogen. This reduction mainly provides compounds of the formula XVII, but also a small amount of various possible isomers, ie compounds of the formulas XVII A, B, C and D. The above reduction stage would remove any N-oxide function in the 4-position and vulnerable groups, see above present as R. (like ITitro or cyan in 7-position), reduce. Such groups can be replaced by methods which are known per se and which are mentioned in this description.

5th stage: Compounds of the formula XVIII are then obtained by reacting compounds of the formula XVII with an acylating agent, for example an alkanecarboxylic acid orthoester of the formula

wherein R has the meaning given in formula I and R is lower alkyl,

taking into account the reaction conditions and parameters related to the direct conversion of compounds of the formula V in compounds of the formula VII are explained on page 25 of this description.

8098 15/1301

6th stage: Compounds of the formula XIX are also obtained by acylating compounds of the formula XVII with a compound of the formula

R ₁ COX or

■ wherein R- has the meaning given in formula I and X means halogen.

Solvents for the above process stage include methylene chloride, ether, chlorinated hydrocarbons and the like, preferably in combination with an acid acceptor, such as organic or inorganic bases such as triethylamine, pyridine
or alkali metal carbonates. The reaction can be above or
be carried out below room temperature, but is preferably carried out at room temperature before. Compounds of the formula XIX can exist in isomeric forms, namely in the "in the following stereochemical structures:

{l · NHCOR ₁ \ * O

<< CO

cor,

OOR C *

XIX-A

609815/1301

■ "- 40 -

7th stage: Compounds of the formula XX are obtained by reacting compounds of the formula XVII with an aldehyde of the formula R-, CHO, in which R- has the meaning given in formula I. Suitable solvents for this reaction stage are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, dimethylformamide, dimethyl sulfoxide, etc. with or without the addition of a water-binding agent, e.g. molecular sieves, above or below room temperature, preferably between room temperature and the reflux temperature of the solvent.

8th stage: Compounds of the formula XX can be converted into compounds of the formula XVIII by in situ oxidation with oxidizing agents such as manganese dioxide, air, oxygen, etc.

9th stage: Compounds of the formula XVIII can also be formed by dehydrogenating compounds of the formula XIX or isomers thereof with simultaneous cyclization with heating. This reaction stage can be carried out with or without a solvent, for example with dimethylformamide, ethylene glycol, hexamethylphosphoric triamide, at a temperature in the range from 100 ⁰ to 300 ⁰ C, preferably 150 0 to 250 ⁰ C, for example 200 C, with or without the addition of catalysts and water-binding agents.

609815/1301

10th stage: Compounds of the formula XXI can be prepared by condensation of a compound of the formula XIII with the anion generated from the acylaminomalone ester. The anion is generated by deprotonating acylaminomalone esters with a suitable strong base such as alkoxides, hydrides or amides of alkali metals or alkaline bromine metals. The reaction of the compounds of formula XIII with the acylaminomalone ester is preferably carried out in a solvent such as hydrocarbons, e.g. benzene, toluene, hexane, ethers, e.g. dioxane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, etc., in a temperature range from below room temperature to 150 ° C , preferably 0 C to 100 C, room temperature being particularly preferred.

11th stage: Compounds of the formula XIX and isomers thereof are obtained by decarboxylation of compounds of the formula XXI with an alkali metal alkoxide in a solvent such as ether, alcohols, dimethyl sulfoxide, dimethylformamide, etc. above or below, but preferably at room temperature.

The following general reaction scheme illustrates several Reactions of the intermediate of formula XVIII to form compounds of formula I. Unless otherwise stated is, in this reaction scheme R means lower alkyl, ' R "and Rp. Have the meaning given in formula ID, R-., R. and Rg have the meaning given in formula I and A has the

609815/1301

25A0522

meaning given in Pormel I and IB. Bs is for the professional It is clear that certain substituents can be attacked during the reactions described below, for example when A is as in Formula IB but such vulnerable groups can be modified before or after the following Reaction sequence is carried out.

609815/1301

Hl

P N \ _COOH

¹ tsp

«Ι-

XVIII

(RCO) ₀ O.-CHJDH A.
XXII

CH ₂ C

^A XXIV

XXIII

809816/1301

Alkali metal alkoxide (ORQ)

h ^ ¹ S-- ^ ₂

LJ

XXVIII

R = any other alkyl or aryl

XXIX

XXX

609815/1301

P ₉ O / Py for RR'-H

N ₃ PO (OC ₆ H ₅ )

h ^N R ^ ^ J-CON-N

609816/1301

NHCOOR

R.

XXXV ^R 5

1) Pd / Ho (

R ₁

2) (RCOI ₂ O

NHCOR

xxxvii:

809815/1301

COOR

R ¹ X

COOR

XVIII XXXIX

HIGH

P oxidation

^ _N 3 e.g. MnO_ AD

XXX

7 ~ U

<C ^ i-C = N-

rV ^R 3

XLI

nr'r "XLII

609815/1301

XLIII

609815/1301

XXXVI

RCO ₃ H

XLV *

- * A is

C = N or - C = N

XLIV

Ac ₂ O

XLVI

A is like " in -XLV

OH

HIGH

MnO,

XLVII

~ A is like in XLV

XLVIII

A is like- in

XCV

609815/1301

ΌΝΗΝΗ

2
ENT ₂

NHCOOR

Ni / H,

NH

, RQH

'NO

LI

'R, is not nitro-substituted

LII

6-0 98 1 S / 13.01:

XVIII »XXII

Compounds of the formula XXIl are formed by hydrolysis of Compounds of the formula XVIII to the corresponding acids with Alkali metal hydroxides, e.g. sodium hydroxide or potassium hydroxide,

XVIII »XXIII

Compounds of the formula XXIII are formed by reducing compounds of the formula XVIII with lithium aluminum hydride or equivalent reducing agents.

XXIII - »XXIV

Compounds of the formula XXIII can be obtained by acylation with acid anhydrides or acid chlorides in the presence of an acid acceptor, such as pyridine., converted into compounds of the formula XXIV will.

XXIII> XXV

Compounds of the formula XXV can by oxidation of compounds of the formula XXIII with known oxidizing agents such as chromium trioxide and manganese dioxide.

XXIII> XXVI

Compounds of the formula XXVI are prepared by adding the hydroxyl group in the 3-position substituent of compounds of the Formula XXIII replaced by halogen. This reaction is carried out with reagents such as phosphorus trichloride or thionyl chloride.

6 0 9 8 15/1301

leads.

XXVI »XXVII, XXVIII and XXIX

In the compounds of the formula XXVI, the halogen can be in the 3-position Nucleophilic substituents are replaced by other nucleophilic groups, for example with amines (XXVII), alkoxides (XXVIII) and cyanides (XXIX).

Compounds of the formula XXX are formed by reaction of the 3-position Aldehyde in formula XXV with an organometallic Reagents such as Grignard reagents or alkyl, or aryl lithium reagents.

XXII or XVIII> XXXI

Compounds of the formula XXXI are formed by direct aminolysis of compounds of the formula XVIII (only primary amines and ammonia) or by converting compounds of the formula XXII into corresponding acid chlorides and their subsequent reaction with a primary or secondary amine or with ammonia.

XXXI »XXXII

Compounds of the formula XXXII are formed by dehydration of compounds of the formula XXXI in which R and R 'are hydrogen are. Dehydration is accomplished with reagents such as phosphorus pentoxide in suitable solvents (such as pyridine).

609815/1301

XVIII or XXII. »XXXIV

Compounds of the formula XXXIV are obtained by direct hydrazinolysis or "Conversion to acid chlorides and subsequent Treatment with a hydrazine.

XXII - »XXXVI

Compounds of the formula XXXVI are obtained by decarboxylation with or without a catalyst and solvent. The decarboxylation is carried out by heating, for example at 150 C to 35O ⁰ C.

XXII »XXXV

Compounds of the formula XXXV are formed by a modified Curtius reaction, i.e. by reaction of compounds of the formula XXII with phosphoryl azides to form azides, i.e. compounds of the formula XXXIII, and subsequent heating this azide with an alcohol, which participates in the reaction.

Compounds of the formula XXXVII are obtained by reacting compounds of the formula XXXV, in which R is benzyl, with palladium and hydrogen to form the free amine, which is then acylated with an acid chloride or acid anhydride.

609815/1301

XXXVI »XXXVIII

Compounds of the formula XXXVIII are obtained by reacting Compounds of formula XXXVI with strong bases and alkoxycarbony chlorides, e.g. potassium tert-butoxide and methyl chloroformate, - Wherein an alkoxycarbonyl group is introduced in the 4-position will.

XVIII »XXXIX

Compounds of the formula XXXIX are formed by alkylating compounds of the formula XVIII with alkyl halides in the "presence" strong bases, e.g. methyl3odide in the presence of Ealiüm-tert.-Batylat.

XXX »XL

Compounds of the formula XL are formed by the oxidation of compounds of the formula XXX, as set out in stage XXIII * XXV.

XXV or XL »XLI

Compounds of the formula XLI are obtained by treating compounds of the formula XXV or XL with a hydrazine of the formula M ₂ M ¹ R ", where R 'and R" are hydrogen, lower alkyl or aryl.

609815/1301

XXV or XL »XLII

• / connections of the formula XLII are formed. Reaction of compounds of formula XXV- or XL .with hydroxylamine or alkoxyamines.

XLII »XLIII

Compounds of the formula XLIII are obtained by reducing compounds of the formula XLII with Raney nickel and hydrogen.

Compounds of the formula XLIV are obtained by reacting compounds of the formula XXXVI with halogenating agents such as bromine, N-bromosuccinimide, N-chlorosuccinimide etc.

XLIV »XLV

Compounds of the formula XLV are obtained by reacting compounds of the formula XLIV with a peracid such as metachloroperbenzoic acid or peracetic acid. If R, is lower alkyl, is obtained by subsequent reaction with an acid anhydride a compound of the formula XLVI.

XLVI »XLVIII

Compounds of the formula XLVIII are obtained by reacting compounds of the formula XLVI with an alkoxide or hydroxide of an alkali metal.

6 09815/1301

XLYIII ÄLVII

Compounds of the formula XLYII form through. Oxidation, as in stage XXII »XXV.

.XLIX-

Compounds of the formula L are obtained by reacting compounds of the formula XLIX with nitrous acid.

“LH

Compounds of the formula LII are formed by the reaction of compounds of formula L as in stage XXXIII «» XXXV.

LII »LI

Compounds of the formula LI are formed by reducing compounds of the formula LII with Raney nickel and hydrogen.

The following reaction scheme shows a process for the preparation of imidazobenzodiazepines, wherein R _{1 is} phenyl, substituted phenyl or pyridyl. The various substituents are defined in the reaction scheme itself ".

609815/1301

■ R _{4 #} Rg are as in formula I. and are as in formula ID R ¹

strong Bas4 ^LVI N — I

Il

C-R

LVI

LIII

R is lower alkoxy or NR ¹ R "where R ', R" are lower alkyl; R, is phenyl, subst. Phenyl or pyridyl.

, R., R ₅ , Rg are as above

are like "" above

^R 6

^Are

609815/1301

Compounds of the formula LV are obtained by reacting a compound of the formula XIII with an ITitron anion, which is produced by reacting a compound of the formula LVI with a strong base such as butyllithium, potassium tert-butoxide, etc. The reaction (XIII- * LV) can be carried out in situ without isolating the intermediates of the formulas LIII and LIV. Solvents suitable for this reaction include hydrocarbons, such as hexane, toluene, etc., ethers, for example tetrahydrofuran, dimethylformamide and dimethyl sulfoxide.

To carry out the cyclization in situ, the reaction temperature should be in the range from -100 ° C. to room temperature, preferably -80 C to 25 0, e.g. -70 C with subsequent heating to room temperature.

Compounds of the formula I, IB, IC, ID and IE and their pharmaceutically acceptable acid addition salts are useful as muscle relaxants, sedatives and anticonvulsants, and many of which are particularly useful when used in intravenous and intramuscular preparations in view of this on the solubility of the acid addition salts in aqueous solutions. ¥ ie this is provided in the present invention, can the new compounds of the formula I and their acid addition salts are incorporated into pharmaceutical dosage forms, which contain about 0.1 to 40 mg, preferably 1-40 mg of active ingredient, the dose of the species and the individual

609815/1301

254D522

needs to be adapted. The new compounds of the formula I, IB, IC, XD and IB and their pharmaceutically acceptable salts can be internal, "for example parenteral or enteral, administered in common pharmaceutical dosage forms. For example, they can be converted into common liquid or solid carriers, such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the like, can be incorporated to deliver tablets, elixirs, capsules, solutions, emulsions and the like using recognized pharmaceutical methods.

In drafting the above description, various articles and TJ.S. Patents cited; so will is intended to incorporate the teaching of these references in order to complete the disclosure.

The new intermediates disclosed in the present specification are also subject of the present invention.

The following examples are intended to illustrate the invention without, however, limiting it. All temperatures are in Degrees Celsius.

609815/1301

example 1

A solution of 200 g (0.695 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in-2 1 of tetrahydrofuran and 250 ml of benzene is added to methylamine with cooling in an ice bath saturated. A solution of 190 g (1 M) titanium tetrachloride in 250 ml benzene is poured through a drip channel for 15 minutes admitted. After the addition has ended, the reaction mixture is heated to reflux for 3 hours. Water (600 ml) is slowly added to the cooled reaction mixture. The inorganic Material is removed by filtration and washed well with tetrahydrofuran. The aqueous phase is separated and the organic phase is dried over sodium sulfate and evaporated. The crystalline residue consists of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine is collected; Melting point 204-206 °. An analytical sample is made from methylene chloride / ethanol recrystallized and shows the melting point 204-206 °.

8.63 g (0.125 M) sodium nitrite is in three portions to a solution of 30.15 g (0.1 M) 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine put in 150 ml of glacial acetic acid. The reaction mixture is stirred for 1 hour at room temperature, then diluted with water and with Extracted methylene chloride. The extracts are washed with saturated sodium bicarbonate solution and dried over sodium sulfate and evaporated, with azeotropic evaporation with toluene at the end. 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine are obtained as a yellow OeI.

This material is dissolved in 100 ml of dimethylformamide, and the solution becomes a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane and 11.1 g (0.1 M) of potassium t-butoxide, which was stirred under nitrogen for 15 minutes. ■ The reaction mixture is stirred for 1 hour at room temperature, then acidified by adding glacial acetic acid, diluted with water

609815/1301

25A0522

and extracted with methylene chloride. The extracts are washed with water, dried over sodium sulfate and evaporated.

Obtained by crystallization of the residue from ether one 7-chloro-1,3-dihydro-5- (2-fluorophenyl) ^ -nitromethylene ^ H-1,4-benzodiazepine from melting point 170-172. An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 174-176 °.

A solution of 16.5 g (0.05 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol is added to 5 teaspoons Raney nickel hydrogenated for 2 1/2 hours at atmospheric pressure. Removal of the catalyst and evaporation gives crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine.

20 ml of acetic anhydride are added to a solution of 12 g of this product in 300 ml of methylene chloride. the Solution is made with 300 ml of 10% aqueous sodium carbonate solution covered, and the two-phase mixture is stirred for 30 minutes at room temperature. The organic phase is separated washed with sodium carbonate solution and dried over sodium sulfate. Evaporation gives crude 7-chloro-2,3-dihydro-5- (2-fluorophenyl) -2-propionylaminomethyl-IH-1,4-benzodiazepine. This product is contained in 50 g of polyphosphoric acid while Heated to 150-170 ° for 10 minutes. The reaction mixture is cooled, dissolved in water and made with concentrated ammonia and Ice made alkaline. The base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel, a 20% solution of methanol in methylene chloride is used as the eluent. The clear parliamentary groups are combined, evaporated and the residue crystallized from ether, 8-chloro-3a, 4-dihydro-1-ethyl-6- (2-fluorophenyl) -3H-imidazoCl, 5-a] [1,4] benzodiazepine obtained from melting point 131-133 °.

6 09815/1301

A mixture of 3.4 g of 8-chloro-Sa, 4-dihydrp-l-ethy1-6- (2-fluorophenyl) -4H-imidazo [l, 5] [l, 4] benzodiazepine, 400 ml of toluene and 30 g of activated manganese dioxide is under for 2 hours Using a water separator heated to reflux. The hangan dioxide is separated off by filtration through Celite and the filtrate is evaporated. Crystallization of the residue from ether gives 8-chloro-1-ethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4-benzodiazepine from melting point 140-143. For analysis purposes this product is recrystallized from ether and shows the melting point 143-145 °.

Example 2

7 ml of acetic anhydride become a solution of 6.16 g crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine given in 200 ml of methylene chloride. The solution is covered with a layer of 200 ml of saturated sodium bicarbonate solution and the mixture is stirred for 20 minutes. The organic phase is separated off with sodium bicarbonate solution washed, dried over sodium sulfate and evaporated. The residue obtained is resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine. This product is heated to 150 ° with 40 g of polyphosphoric acid for 10 minutes warmed up. The cooled reaction mixture is dissolved in water, Made alkaline with ammonia and ice and extracted with methylene chloride. The extracts are dried and evaporated. The residue is chromatographed on 120 g of silica gel, using a 20% solution of methanol in methylene chloride as the eluent is used. The clear fractions are purified and evaporated and give resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. A mixture of this product with 500 ml of toluene and 30 g Manganese dioxide is refluxed for 1 1/2 hours. The manganese dioxide is removed by filtering through Celite. The filtrate is evaporated and the residue from ether crystallized, whereby 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [l, 5-a] [l, 4] benzodiazepine from melting point 152-154

B0981B / 1301

2b40522

receives. An analytical sample is recrystallized from methylene chloride / hexane

Example 3

152.5 g (0.5 M) 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepin-2-one saturated with methylamine are as described in the first paragraph of example 1 with 133 g (0.7 M) Titanium tetrachloride in 2 l of tetrahydrofuran and 400 ml of benzene are added to give 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-1,4-benzodiazepine with a melting point of 216-219 °. An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 217-219 °.

10 g (0.145 M) sodium nitrite are added for 45 minutes portionwise to a solution of 22.4 g (0.07 M) 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-1,4-benzodiazepine put in 150 ml of glacial acetic acid. After the addition has ended, the reaction mixture is stirred for a further 20 minutes under nitrogen. That Product is precipitated by the addition of ice water, collected and dissolved in toluene. The solution becomes saturated with Washed sodium bicarbonate solution, dried and evaporated under reduced pressure. The resulting yellowish viscous According to the thin-layer chromatogram, OeI mainly consists from the desired nitrosoamidine. This material is dissolved in ml of dimethylformamide and added to a mixture of 30 ml Nitromethane, 100 ml dimethylformamide and 10 g potassium t-butoxide given. The reaction mixture is slowly heated to 85 ° while stirring and passing a stream of nitrogen through it. To The reaction mixture is cooled for 5 minutes and acidified by adding 10 ml of glacial acetic acid. The product is gradual Addition of water crystallizes with seeding (the seed crystals are obtained by chromatography over silica gel under Using a 10% solution of ethyl acetate in methylene chloride as a flow agent). The precipitated crystals are collected, washed with water and recrystallized from methylene chloride / ethanol and yield 7-chloro-5- (2-chloro-

80981B / 1301

if

phenyl) -1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine vom Melting point 182-185 °.

By hydrogenating 7 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine for 1 hour in 300 ml of tetrahydrofuran and 150 ml of methanol in the presence of 5 teaspoons of Raney nickel, crude 2-aminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-IH-1,4-benzodiazepine is obtained. This product is acetylated in the usual way and gives oily 2-acetaminomethyl-7-chloro-5- (2-chlorophenyl) -2,3-dihydro-IH-1,4-benzodiazepine, which is heated to 140-150 ° in 15 g of polyphosphoric acid for 10 minutes. The usual work-up provides a yellow resin which is chromatographed on 250 g of silica gel, a 20% solution of methanol in Methylene chloride is used as a flow agent.

The clear fractions give resinous 8-chloro-6- (2-chlorophenyl) -3a, 4-dihydro-1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine. This product is oxidized with 10 g of manganese dioxide in 200 ml of toluene. After refluxing for 1 1/2 hours the manganese dioxide filtered off and the filtrate evaporated. Crystallization of the residue from ether gives 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point of 140-144 °. For analytical purposes, the product is recrystallized from methylene chloride / hexane and shows' the melting point 142-144 °.

Example 4

A solution of 94.6 g (0.3 M) 5- (2-chlorophenyl) -1, 3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one in 2 l of tetrahydrofuran and 300 ml of benzene is saturated with methylamine while cooling in ice water. A drip channel is then used Solution of 40.2 ml (0.36 M) titanium tetrachloride in 300 ml benzene was added. When the addition is complete, the reaction mixture becomes heated to reflux with stirring for 3 hours. 300 ml of water are slowly added to the cooled reaction mixture.

609815/1301

give. The inorganic solids are removed by filtration and washed well with tetrahydrofuran. The water is removed from the filtrate and the organic phase is dried over sodium sulfate and evaporated. The residue will Chromatographed on 500 g of silica gel, a 10% solution of ethanol in methylene chloride is used as a flow agent. By crystallizing the clear fractions from methylene chloride / ethanol 5- (2-chlorophenyl) -7-nitro-2-methylamino-3H-1,4-benzodiazepine is obtained as a yellow product with a melting point of 219-221 °.

8.63 g (0.125 M) sodium nitrite are added for 15 minutes in three portions to a solution of 33.9 g (0.1 M) 5- (2-chlorophenyl) -7-nitro-2-methylamino-3H-1,4-benzodiazepine put in 200 ml, glacial acetic acid. After the addition is complete for 1 1/2 Stirring for hours at room temperature and the product precipitated by adding water. The yellow solid is collected, washed with water, sucked dry and recrystallized from ethanol, 5- (2-chlorophenyl) -7-nitro-2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine obtained in the form of yellow crystals with a melting point of 164-166 °. An analytical one The sample is recrystallized from methylene chloride / ethanol and has a melting point of 167-169 °.

A mixture of 3.58 g (0.01 M) 5- (2-chlorophenyl) -7-nitro-2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine, 20 ml dimethylformamide, 5 ml nitromethane and 1.3 g (0.0115 M) potassium butoxide is stirred under nitrogen for 15 minutes at room temperature. After adding 2 ml of glacial acetic acid, the Reaction mixture distributed between methylene chloride and water. The organic phase is washed with water over sodium sulfate dried and evaporated. The residue is chromatographed on 80 g of silica gel, a 10% solution of Ethyl acetate in methylene chloride is used as a flow agent. By crystallizing the clear fractions from methylene chloride / Ethanol gives 5- (2-chlorophenyl) -l, 3-dihydro-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine as straw-colored crystals

80981 S / 1301

-'66 -

of melting point 240-243 ° (dec.).

Example 5

A solution of 33 g (0.1 M) 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide in 100 ml of dimethylformamide is added to a mixture of 50 ml of nitromethane, 12.5 g (0.11 M) of potassium t-butoxide and 100 ml of dimethylformamide. The reaction mixture is stirred for 1 hour while nitrogen is passed through. After adding 10 ml of glacial acetic acid, it becomes the product crystallizes by gradually adding 250 ml of water. The precipitated yellow material is collected with Washed water, methanol and ether and gives 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4-oxide of melting point 253-255 ° (dec.). An analytical sample is recrystallized from methylene chloride and shows the same Melting point.

5 teaspoons of Raney nickel become a solution of 16.5 g (0.05 M) T-chloro-ljS-dihydric ^ -nitromethyler.-S-phenyl-2H-1,4-benzodiazepine-4-oxide given in 500 ml of tetrahydrofuran and 250 ml of methanol. The mixture is for 5 hours hydrogenated at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. Of the The residue is dissolved in 2-propanol and the solution is made strongly acidic with ethanolic hydrochloric acid. After evaporation part of the solvent crystallizes out the dihydrochloride of the desired product. The orange crystals will be collected and provided 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine dihydrochloride from a melting point of 230-240 °.

10 ml of acetic anhydride are added to a solution of 10 g of this product in 50 ml of water and 50 ml of methanol. 100 ml of a 10% strength aqueous solution of sodium carbonate are added over a period of 5 minutes with stirring. After finished The addition is stirred for a further 10 minutes, whereupon

60981S / 13Ö1

extracted with methylene chloride. The extracts are washed with sodium carbonate solution, dried over sodium sulfate and evaporated, with zurr. Final azeotropic evaporation with toluene. 2-Acetaminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-1 _f 4-benzodiazepine is obtained as a yellow resin.

This product is heated to 135-140 ° in 50 g of polyphosphoric acid for 10 minutes. The initially orange color the reaction mixture changes to a light yellow. The cooled reaction mixture is dissolved in water with concentrated Ammonia and ice made alkaline and extracted with methylene chloride. The extracts are dried and evaporated. The yellow resin is dissolved in 2-propanol and treated with ethanolic hydrochloric acid, with colorless dihydrochloride of the desired product crystallized out. This product has a melting point of 240-245 °.

The dihydrochloride obtained above is between methylene chloride and aqueous ammonia distributed. The organic phase is dried and evaporated. By crystallizing the A residue from ether gives e-chloro-Sa ^ -dihydro-1-methyl-6-phenyi-3H-imidazo [1,5-a] [1,4-benzodiazepine as a colorless product with a melting point of 116-118.

A mixture of 3.1 g (0.01 M) 8-chloro-3a, 4-dihydro-imethyl-6-phenyl-3H-imidazo [l, 5-a] [l, 4] benzodiazepine, 20 g of activated manganese dioxide and 150 ml of toluene are heated to reflux for 1 hour. The manganese dioxide is obtained by filtering removed by celite and washed well with methylene chloride. The filtrate is evaporated and the residue from ether crystallized, with 8-chloro-l-methyl-6-phenyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine obtained as colorless crystals with a melting point of 187-188 °.

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Example 6

A mixture of 11.2 g (0.1 M) potassium tert-butoxide, 50 ml nitroethane and 200 ml dimethylformamide is stirred for 15 minutes at room temperature. A solution of 29 g (0.088 M) of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-l _/ 4-benzodiazepine in 100 ml of dimethylformamide is added with stirring and under a nitrogen atmosphere, whereupon stirred for a further 6 hours under a nitrogen atmosphere. The reaction mixture is neutralized by adding glacial acetic acid and diluted with water. The product is extracted with ether. The extracts are washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. Crystallization from ether gives 7-chloro-1,3-dihydro-.5- (2-fluorophenyl) -2- (1-nitroethylene) -2H-1,4-benzodiazepine as yellow crystals with a melting point of 136-142 ° .

5 teaspoons of Raney nickel become a solution of 17.3 g (0.05 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitroethylene) -2H-l, 4-benzodiazepine given in 750 ml of tetrahydrofuran. The mixture is left for 4 hours at atmospheric pressure hydrogenated. The catalyst is separated by filtration through Celite and washed well with methanol. The filtrate will evaporated and gives crude 2- (1-aminoethyl) -7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine as a reddish oil.

This product is dissolved in 300 ml of methylene chloride. After adding 14 ml of acetic anhydride, 300 ml of saturated aqueous Sodium bicarbonate solution was added and the two-phase mixture was stirred for 1 hour at room temperature. The methylene chloride phase is separated off, washed with bicarbonate solution, dried over sodium sulfate and evaporated. The residue is heated to 160-170 ° for 10 minutes with 40 g of polyphosphoric acid. The cold reaction mixture is diluted with water, Made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts are mixed with water

609815/1301

wash, dry and evaporate to give a brown residue, which is chromatographed on 250 g of silica gel, a 20% solution of methanol in methylene chloride is used as the eluent. The thin-layer chromatography Uniform fractions are collected and yield a resin which is subjected to the subsequent oxidation.

A mixture consisting of this material, 20 g of activated manganese dioxide and 300 ml of toluene is on for 3 hours Heated to reflux using a water separator to remove the water. The manganese dioxide is obtained by filtering removed by celite and washed well with methylene chloride. The filtrate is evaporated and the residue through with pressure 150 g of silica gel H chromatographed, a 3% solution of ethanol in methylene chloride being used as the eluent will. The main component eluted first is 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine.

This product was converted into a crystalline dihydrochloride by treatment with ethanolic hydrochloric acid in ether Melting point 247-250 ° (decomp.).

The more polar component is crystallized from methylene chloride / ether / hexane and gives 8-chloro-1,3-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine from melting point 178-180 °.

Example 7

A mixture of 3.1 g (0.01 M) e-chloro-l-methyl-ö-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 2.15 g (0.0125 M) of m-chloroperbenzoic acid and 100 ml of methylene chloride are added for 48 hours stirred at room temperature. The reaction mixture is then washed with a 10% strength aqueous sodium carbonate solution and water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is on 80 g of silica gel chromatographed, a 10% solution of ethanol in

80 9815/1301

~ 70 -

Methylene chloride is used as a flow agent. The thin-layer chromatography uniform fractions are combined and evaporated. By crystallizing the residue 8-chloro-1-methyl-6-pheny1-4H-imidazo [1,5-a] is obtained from methylene chloride / ether [1,4] benzodiazepine-5-oxide with a melting point of 260-261 °.

Example 8

A solution of 1 g of S-chloro-l-methyl-ö-phenyl ^ H-imidazo- [1,5-a] [1,4] benzodiazepine-5-oxide in 20 ml of acetic anhydride is heated on the steam bath for 24 hours. The reaction mixture is evaporated under reduced pressure and the residue is crystallized from ether, 4-acetoxy-8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point of 200-201 °.

Example 9

0.54 g of sodium methoxide become a solution of 0.73 g (2 mmol) 4-ACe ^ Xy-S-Chlor-1-methyl-e-phenyl ^ H -imidazo [1,5-a] [1,4] benzodiazepine given in 20 ml of methanol. The reaction mixture is for 30 minutes at room temperature left to stand, whereupon, after neutralization with acetic acid, the solvent is evaporated under reduced pressure. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is over sodium sulfate dried and evaporated. Crystallization of the residue from ether gives 8-chloro-4-hydroxy-1-methyl-6-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine from melting point 173-174 °.

609816/1301

Example 10

A warm solution of 6.5 g (O _f O2 M) 8-chloro-6- {2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 30 ml Ethanol is combined with a warm solution of 2.6 g (0.022 M) of maleic acid in 20 ml of ethanol. The mixture is diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the precipitated crystals are collected, washed with ether, dried in vacuo and t provide 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [l, 4] benzodiazepine maleate with a melting point of 148-151 °.

Example 11

A mixture of 17.4 g (0.05 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (1-nitromethylene) -2H-1,4-benzodiazepine-4-oxide , 500 ml of tetrahydrofuran, 200 ml of methanol and 5 teaspoons of Raney nickel is for 5 hours at atmospheric pressure hydrogenated. The catalyst is removed by filtration and the filtrate is evaporated, with azeotropic at the end Xylene is evaporated. The residue obtained is crude 2-aminomethyl-7-chloro-5- (2-fluorophenyl) -2,3-dihydro-IH-1,4-benzodiazepine.

This product is dissolved in 200 ml of ethanol, and the solution is after addition of 14 ml of triethyl orthoacetate and 2.8 g of p-toluenesulfonic acid were heated to reflux for 2 hours. The solvent is removed under reduced pressure and the residue is between methylene chloride and a 10% aqueous sodium carbonate solution distributed. The organic phase is dried and evaporated and gives oily 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methy1-3H-imidazo- [1,5-a] [1,4] benzodiazepine. This crude product is dissolved in 500 ml of xylene. After adding 50 g of activated manganese dioxide the reaction mixture is heated to reflux for 1 1/2 hours, the water being removed using a water separator will. The inorganic material is removed by filtration

609815/1301

and the filtrate is evaporated and yields 10 g of a brown oil. A warm solution of 4.65 g (0.04 M) of maleic acid in 50 ml of Aethanoi is added to this residue. When the solution is complete the product is made by adding Aether crystallized out. The crystals are collected, washed with ether and yield 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate from a melting point of 112-115 °. By heating in vacuo to 90-100 °, this product is converted into a product with a higher melting point of 148-151 ° convicted.

Example 12

A solution of 0.32 g (1 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in 5 ml Aethanoi is treated with an excess of ethanolic hydrochloric acid. The salt is crystallized out by adding 2-propanol and ether. The colorless crystals are collected, Washed with ether, dried and give 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine dihydrochloride from melting point 290-295 °.

Example 13

A solution of 0.325 g (1 mmol) of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 3 ml of Aethanoi is with a suspension of 0.4 g (1 mmol) of the dihydrochloride this compound combined in 5 ml of Aethanoi. After filtering, the solution is treated with ether and allowed to crystallize heated for 5 minutes on the steam bath. The crystals are collected, washed with ether, dried and delivered 8-Chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5 ^ a] [1,4] -benzodiazepine hydrochloride from melting point 295-297 °.

809815/1301

Example 14

A solution of 23.6 g (0.10 mol) 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran (containing approximately 20 moles of monomethylamine) is cooled in an ice bath. 14 ml (d = 1.73, "0.125 mol) are added to this mixture Titanium tetrachloride was added to 200 ml of benzene.

The reaction mixture is for 2 days at room temperature touched. The titanium complex is destroyed by adding 20 ml of water. The precipitated inorganic salts are removed by filtration. The solvent is evaporated in vacuo and the residue is partitioned between methylene chloride and water distributed. A colorless amorphous solid consisting of 2-methylamino-5-phenyl-3H-1,4-benzodiazepine with a melting point 227-229 ° is removed by filtration. After drying over sodium sulfate, the methylene chloride mother liquor gives Evaporation and crystallization from ethyl acetate another sample of a colorless solid with a melting point of 226-228 °.

An analytical sample is made from dimethylformamide; ai:
227-229 ⁽

crystallizes and gives colorless crystals with a melting point

To a stirred solution, cooled to 10 °, of 10.0 g (0.04 M) of 2-methylamino-5-phenyl-3H-1,4-benzodiazepine in 100 ml Pyridine is added to 100 ml of a saturated solution of nitrosyl chloride in acetic anhydride. The solution is during 3.5 Stirred for hours and brought to ambient temperature during this time. The solution is poured onto 300 ml of ice water and the aqueous solution is extracted five times with 150 ml of methylene chloride. The combined organic extracts are with Washed water and brine and dried with calcium sulfate. After removing the solvent under reduced pressure a black semi-solid residue is obtained. This residue is chromatographed on 500 g of silica gel (chloroform elution) and gives 2- (N-nitrosomethylamino) -5-phenyl-3H-

6098 1 S / 1301

1,4-benzodiazepine, melting point 192-199 ° (decomp.). This Product is used in the following stage:

By treating 50 ml of nitromethane in 200 ml of dimethylformamide with 5.7 g (0.05 M) of potassium t-butoxide, the conjugate base of nitromethane. The yellow suspension obtained is stirred and with 10.9 g of crude. 2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine treated in 100 ml of dimethylformamide. The dark mixture thus obtained is during Heated for 2 hours at 25 ° and for 1 hour at 85 ° and then cooled to 25 ° and poured into 1 liter of water. To Acidification with acetic acid, the aqueous solution is extracted four times with 250 ml of methylene chloride. The united organic Extracts are washed with water and brine, dried with calcium sulfate and evaporated in vacuo. Received as residue a dark oil, which on 1 kg silica gel (chloroform elution) is purified and crude 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine with a melting point of 131-142 °. An analytical sample is made by recrystallization made from ethanol and has a melting point of 141-142.

A mixture of 8.4 g (0.03 M) 1,3-dihydro-2-nitromethylene-5-pheny1-2H-1,4-benzodiazepine, 75 ml of tetrahydrofuran, 75 ml of methanol and 2 teaspoons of Raney nickel are added for 6 hours hydrogenated at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated to give crude 2-aminomethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine.

This product is dissolved in 50 ml of methylene chloride and stirred for 15 minutes with 6 ml of acetic anhydride and 200 ml Treated saturated aqueous sodium bicarbonate solution. The methylene chloride phase is separated off, washed with bicarbonate solution, dried and evaporated. The residue is heated to 130-150 ° for 15 minutes with 25 g of polyphosphoric acid. The cool reaction mixture is between water and Aether distributed. The aqueous phase is made alkaline with ammonia and extracted with methylene chloride. The extracts

609815/1301

. 75 -

are dried and evaporated. By chromatography of the residue on 70 g of silica gel, a 20% solution of Aethanoi in methylene chloride is used as a flow agent, one obtains 3a, 4-dihydro-l-methyl-6-pheny1-3H-imidazo [1,5-a] [1,4] benzodiazepine as a light yellow resin.

This product is refluxed in 50 ml of toluene with 7 g of activated manganese dioxide for 1 1/2 hours. The inorganic material is filtered off and the filtrate is evaporated. The residue is chromatographed on 30 g Purified silica gel, a 10% solution of ethanol in methylene chloride being used as the eluent. The clear ones Fractions are combined and evaporated. Crystallization of the residue from ether gives 1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine from a melting point of 180-182 °.

Example 15

To a stirred solution of 6 g (0.02 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2H-1,4-benzodiazepin-2-one 1.05 g (0.25 M) of a 57% sodium hydride dispersion in mineral oil are added to 100 ml of dry tetrahydrofuran. The reaction mixture is refluxed under argon for 1 hour. After cooling to room temperature, the Reaction mixture treated with 7.4 g (0.03 M) dimorpholine phosphinic acid chloride and treated for a further 2 hours under argon at room temperature touched. The reaction mixture is filtered, evaporated under reduced pressure to give a gummy Residue. By stirring this gum with 100 ml of anhydrous ether, white crystals are obtained, which are filtered off collected, washed with a little ether and air-dried. The 7-chloro-2-di- (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -S-methyl-SH-l ^ -benzodiazepine thus obtained shows a melting point of 90-95 °.

609815/1301

A stirred solution of 2.4 g (0.04 M) nitromethane in. 50 ml of dry dimethylformamide is mixed with 1 g (0.024 M) of a 57% sodium hydride dispersion under argon at room temperature treated in mineral oil .. The reaction mixture is stirred for 1 hour at room temperature and then with 5.2 (0.01 M) 7-chloro-2-di (morpholino) -phosphinyloxy-5- (2-fluorophenyl) -3-methyl-3H-1,4-benzodiazepine added, whereupon the mixture was stirred for a further 24 hours at room temperature and under argon will. The dark mixture is poured onto a mixture of ice and glacial acetic acid and gives a yellow one with stirring Solid. Stirring is continued until all of the ice has melted. The solid is filtered, washed with water, on Air-dried and gives 7-chloro-1,3-dihydro-6- (2-fluorophenyl) -3-methyl-2-nitromethylene-2H-1,4-benzodiazepine of melting point 215 ° (decomp.). Recrystallization of a sample from methanol / methylene chloride (1: 1) gives yellow needles with a melting point 219-221 ° (dec.).

A solution of 5.2 g (0.015 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methyl-2-nitromethylene-2K-1,4-benzodiazepine in 450 ml of tetrahydrofuran / methanol (2: 1) for 3 hours using a Parr apparatus, 3 teaspoons of Raney nickel and an initial pressure of 18 psi. The reaction mixture is filtered, evaporated under reduced pressure and provides crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -3-methyl-1H-1,4-benzodiazepine as a yellow OeI.

The crude aminomethyl compound is mixed with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml Mixed ethanol. After refluxing for 2 hours, the solvent is evaporated under reduced pressure. Of the The residue is cooled to room temperature, treated with a mixture of ice and concentrated ammonium hydroxide and treated with Extracted methylene chloride. Evaporation of the dried extracts gives crude 8-chloro-3a, 4-dihydro-1,4-dimethyl-6- (2-fluorophenyl) -3H-imidazo [1,5-a] [1,4] benzodiazepine as rubber.

809815/1301

The crude dihydroimidazobenzodiazepine is active with 20 g. fourth manganese dioxide and 200 ml of toluene mixed and during Heated to reflux for 2 hours. The manganese dioxide is removed by filtration and washed with methylene chloride. By Evaporation of the combined filtrates and washing liquids under reduced pressure gives a brown gum. By Stirring this gum for a few minutes with ethanolic hydrochloric acid gives 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazoC1,5-a] [1,4] benzodiazepine dihydrochloride as a white powder. The salt melts at 247-250 °.

Example 16

■ 3 g of zinc dust become a solution of 2.8 g of 8-chloro-6- • (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine given in 75 ml of methylene chloride and 75 ml of glacial acetic acid. The reaction mixture is stirred for 2 hours at room temperature, whereupon the inorganic material is filtered off and washed with methylene chloride and water. The filtrate will diluted with 100 ml of methylene chloride and 200 ml of water and made alkaline with ammonia. The methylene chloride phase is separated, dried and evaporated. Crystallization of the residue from ether / hexane gives 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -1-methy1-4H-imidazo Cl, 5-a] [1,4] -benzodiazepine, melting point 200-203 °.

Example 17

A mixture of 100 g (0.8 M) chloroacetaldehyde dimethylacetal and 100 ml of 1.5N hydrochloric acid is heated to reflux for 15 minutes and then cooled, whereupon a solution is made of 130 g (0.5 M) 2-amino-2'-fluoro-5-nitrobenzophenone and 46 g (0.28 M) hydroxylamine sulfate and 1 liter of ethanol are added. The reaction mixture is stirred for 2 hours at room temperature and then heated to reflux for 1.5 hours. That The reaction mixture is cooled and the product obtained by filtration. By recrystallization of the residue from a

609815/1301

A mixture of chloroform and methanol gives pure 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-1,2-dihydroquinazoline-3-oxide as yellow prisms with a melting point of 220-224 °.

A solution of 142 g (0.42.3 M) 2-chloromethyl-4- (2-fluorophenyl) -6-nitro-1,2-dihydroquinazoline-3-oxide in 2.3 1 dichloromethane is treated with 400 g of manganese dioxide and during Stirred for 18 hours after which the solution is filtered. That Manganese dioxide is mixed with 600 ml of tetrahydrofuran and 600 ml of dichloromethane washed. The combined filtrates are concentrated to 400 ml, and 1 liter of ether is added. By cooling and Filtration gives 2-chloromethyl-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide. A sample is recrystallized from a mixture of dichloromethane and methanol and gives pure Product as pale yellow prisms with a melting point of 127-130.

To 500 ml of dimethyl sulfoxide and 75 ml (1.4 M) nitromethane 15.6 g (0.673 M) lithium amide are added with stirring and nitrogen. After 30 minutes the solution is cooled to 5 ° and slowly with 104 g (0.31 M) 3-chloromethyl 1-4- (2-fluorophenyl) -6-nitroquinazoline-3-oxide added, the temperature being kept below 8. The reaction mixture is 68 hours at Allowed to stand at room temperature and then poured onto a mixture of 2.5 l of ice water and 25 ml of acetic acid, whereupon the Solution is filtered. The gum obtained is dissolved in 1 liter of dichloromethane, washed with dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from ethyl acetate and provides 1,3-dihydro-5- (2-fluorophenyl) ^ -nitro ^ -nitromethylene-2H-1,4-benzodiazepine-4-oxide. The filtrates are evaporated, dissolved in dichloromethane and filtered through Florisil. That Florisil is with dichloromethane (600 ml), ether (600 ml) and Ethyl acetate (1.2 l) eluted. The ether and ethyl acetate fractions are combined, concentrated and deliver further end products. A sample is made from a mixture of tetrahydrofuran and hexane recrystallizes and gives pure product in the form of yellow prisms with a melting point of 216-220 °.

609815/1301

A suspension of 25 g (0.0698 M) 1,3-dihydro-5- (2-fluorophenyl) -T-nitro - ^ - nitromethylene ^ H-1,4-benzodiazepine-4-oxide in 1.3 l of absolute ethanol, 10 teaspoons of Raney nickel are added hydrogenated for 9 hours at room temperature and atmospheric pressure. The mixture is filtered through Celite, whereupon the filtrate is evaporated to dryness * A sample of the obtained Oil is crystallized from tetrahydrofuran and gives the intermediate 7-amino-2-aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine as yellow prisms with a melting point of 185-192 ° (decomp.).

The OeI obtained in this way is used without further purification during Hours in a solution of 300 ml of absolute ethanol containing 4.5 ml (0.0257 M) of ethanolic hydrochloric acid and 50 g (0.309 M) triethyl orthoacetate heated to reflux. The reaction mixture is then evaporated to dryness. The residue is dissolved in 150 ml of dichloromethane, washed with 100 ml of dilute ammonium hydroxide, and dried over anhydrous sodium sulfate and evaporated to dryness.

The oil obtained as residue, which crude 8-Acetylaiftino-3a, 4-dihydro-6- (2-fluorophenyl) -1-methyl-3H-imidazo ti / 5-a] [1,4] benzodiazepine represents, is dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The reaction mixture is refluxed for 9 hours while stirring, using a water separator. A further 25 g of activated manganese dioxide are added, whereupon during is heated to reflux for a further 4 hours. The manganese dioxide is removed by filtration and with 500 ml of tetrahydrofuran washed. The filtrates are combined and evaporated to dryness. The oil obtained as residue, which is 8-acetylamino-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine represents, is dissolved in 75 ml of methanol and treated with an excess of ethanolic hydrochloric acid. After 10 minutes 100 ml of water and after a further 20 minutes, in which the 8-acetyl group is hydrolyzed, a mixture of ice and dilute ammonium hydroxide added until the reaction mixture

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-.80-

is basic. The reaction mixture is filtered and the Precipitate and the filtrates are extracted separately with dichloromethane. The extracts are dried and evaporated. The extract from the filtrates is crystallized from isopropanol and gives 8-amino-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine isopropanol. The extracts from the precipitate are chromatographed on Florisil, first containing dichloromethane, then ether and ethyl acetate 10% methanol can be used as the eluant. More is obtained by evaporation and crystallization from isopropanol End product. By recrystallizing the combined products from isopropanol, white rods with a melting point are obtained 135-145 °.

Example 18

A mixture of 17 g (0.05 M) racemic 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) ^ 4H-imidazo [1,5-a] [1,4] benzodiazepine which was freed from the dihydrochloride by partitioning between methylene chloride and aqueous ammonia, 18.8 g (0.05 M) Ο, Ο'-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol is used up cooked to a complete solution. The solution is left to stand overnight for crystallization. The precipitated crystals are collected, washed with ethanol and ether and provide the Ο, Ο'-dibenzoyl-d-tartrate with a melting point of 140-142 °. Recrystallization from ethanol / ether gives a

2! ¹ D

Product with a melting point of 141-142 °; Ca] J = -43.39 ° (c = 1% in methanol).

A solution of 1.6 g (0.0106 m) of! -Tartaric acid in 11 ml Ethanol becomes a solution of 3.5 g of the left-turning base, which has been freed from the above Ο, Ο'-dibenzoyl-d-tartrate, given in 11 ml of ethanol. The crystals obtained are collected, washed with ethanol and ether and give (+) - 8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] -benzodiazepine-d-tartrate from melting point 178-180 °. A product is obtained by recrystallization from ethanol

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- 31 -

Melting point 183-185 °; [α] ^ ⁵ = + 25.69 ° (c = 1.012% in methanol). The amorphous base from which this salt has been removed is shown

2 ^ς ο an optical rotation of [α] ″ = -36.74 (c = 0.939% in methylene chloride).

Example 19

After separating the crystalline salt with 0,0'-dibenzoyl-d-tartaric acid The mother liquor obtained (as described in the previous example) is evaporated and partitioned converted back into the base between aqueous ammonia and methylene chloride. The methylene chloride solution is over sodium sulfate dried and evaporated to give some of the base freed again.

A solution of 9.7 g (0.029 M) of this material in 15 ml of ethanol is treated with a solution of 4.4 g of d-tartaric acid in 14 ml of ethanol. The crystals, which precipitate after many hours, are collected and give (-) - 8-chloro-1,4-dimethyl-6- (2- fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine -d-tartrate with a melting point of 176-178 ^υ . Recrystallization from ethanol gives a product with a melting point of 182-184 °; - Ec] ₀ = -24.96 ° (0.9616% in methanol). The amorphous base freed from this salt shows an optical rotation of [oc1 _D = +37.6 (c = 1.0% in methylene chloride).

Example 20

A solution of 19.3 g (0.06 M) 1,3-dihydro-7- (2-methyll, 3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one in 300 ml of dry tetrahydrofuran is under an argon atmosphere with 3.1 g (0.075 M) of a 57% sodium hydride suspension in mineral oil. The reaction mixture is on for 1 hour Heated to reflux, cooled to room temperature and then admixed with 22.2 g (0.087 M) dimorpholinophosphinic acid chloride. That The reaction mixture is stirred for 2 hours at room temperature and then left to stand overnight. The sodium chloride

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is removed by filtration, whereupon the filtrate from the solvent is released. Crystallization of the residue from ether gives crude 7- (2-methyl-1,3-dioxolan-2-yl) -2- [bis (morpholino) phosphinyloxy] -5-phenyl-3H-1,4-benzodiazepine.

A mixture of 100 ml of dry N, N-dimethylformamide and 6.8 g of nitromethane is treated under a nitrogen atmosphere with 2.8 g (0.066 M) of a 57% suspension of sodium hydride in mineral oil. The mixture is stirred for 1 hour at room temperature and then with a solution of 18 g (0.033 M) of crude 7- (2-methyl-1,3-dioxolan-2-yl) -2- [bis (morpholino) -phosphinyloxy ] -5-phenyl-3H-l, 4-benzodiazepine in 50 ml of dry Ν, Ν-dimethylformamide added. The reaction mixture is allowed to stand for 15 hours at room temperature, after which the dark viscous liquid is poured onto a mixture of ice and dilute acetic acid. The light yellow precipitate is removed by filtration and dissolved in dichloromethane. The solution is washed with dilute ammonium hydroxide and water, dried over sodium sulfate and evaporated. The original filtrate is extracted with dichloromethane and then washed, dried and evaporated as above. The two crude residues are combined and chromatographed on Florisil. Dichloromethane containing 10% ether is used as the eluent. The fractions are through thin-film. Chromatography is monitored and several fractions containing the desired product are collected and evaporated. Crystallization and recrystallization from a mixture of dichloromethane and hexane gives pure _2r 3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) ^ - nitromethylene-S-phenyl-1H-1, A - benzodiazepine as pale yellow prisms with a melting point of 158-161

5 g (0.0137 M) 2,3-dihydro-7- (1-methyl-1,3-dioxolan-2-yl) -2-nitromethylene-5-phenyl-1H-1,4-benzodiazepine in 250 ml of absolute ethanol are during.3,5. Hours in the presence of 1 teaspoon of Raney nickel hydrogenates and provides raw 2-aminomethyl "-2,3-dihydro-7- (l-methyl-l, 3-dioxolan-2-yl) -5-phenyl-1H-1,4-benzodiazepine. To a solution of 4 g (0.0119 M) of this

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Compound in 75 ml of absolute ethanol, 0.7 g (0.0037 M) p-toluenesulfonic acid and 6 g (0.037 M) triethyl orthoacetate added. The reaction mixture is refluxed for 2 hours and then concentrated to dryness. The residue is dissolved in 50 ml of dichloromethane. The solution is with 25 ial diluted ammonium hydroxide, dried over anhydrous sodium sulfate, evaporated and gives crude 3a, 4-dihydrol-methyl-8- (l-methyl-1,3-dioxolan-2-yl) -e-phenyl-SH-imidazo- [1, 5-a] [1,4] benzodiazepine in the form of an OeI. A solution containing 3.8 g (0.0105 M) of this crude oil and 18 g of activated Manganese dioxide in 100 ml of toluene is heated to reflux for 2 hours while stirring, using a water separator will. The reaction mixture is filtered and washed with a mixture of 250 ml of dichloromethane and 250 ml of tetrahydrofuran. . The filtrate is evaporated and dissolved in a small amount of isopropanol and mixed with 1.4 g (0.0121 M) maleic acid in Treated ethanol. The precipitate obtained after the addition of ether is filtered and made from a mixture of methanol / ether recrystallizes and gives 1-methyl-8- (2-methy1-1.3-dioxolan-2-yl) -6-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate methanol (2/1) in the form of whitish prisms with a melting point of 179-182 °.

Example 21

A solution of 0.3 g (0.1000607 M) l-methyl-8- (2-methyll, 3-dioxolan-2-yl) -6-phenyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine maleate-methanol (2/1) in 10 ml (0.01 M) IN hydrochloric acid is left to stand for 18 hours. One adds .a small one Amount of activated charcoal and filtered the reaction mixture. The solution is made basic with ammonium hydroxide, with 25 ml of dichloromethane extracted, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in isopropanol dissolved and treated with 0.35 g (0.10015 M) picric acid in 5 ml of ethanol. The solution is evaporated and the residue obtained is crystallized from methanol. Recrystallization of the mixture from tetrahydrofuran and isopropanol gives

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8-Acetyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine dipicrate as yellow prisms with a melting point of 225-230 °.

Example 22

A solution of 1 g (0.00317 M) S-acetyl-1-methyl-δ-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine dipicrate in 75 ml of absolute ethanol is treated with 0.78 g (0.0205 M) of sodium borohydride. After 18 hours the solution is evaporated to dryness. The residue is acidified with dilute acetic acid, with Ammonium hydroxide made basic and extracted with 75 ml of dichloromethane. The organic phases are combined over dried anhydrous sodium sulfate and evaporated to dryness. The oil obtained as a residue is dissolved in isopropane . Dissolved and treated with 1.6 g (0.007 M) picric acid in 20 ml of ethanol. The precipitated salt is filtered off and twice recrystallized from methanol. 8- (1-Hydroxyethyl) -1-methyl-6-pheny1-4H-imidazo [1,5-a] is obtained [1,4] benzodiazepine dipicrate as yellow rods with a melting point of 223-225 °.

Example 23

The filtrates from the reaction according to Example 22 are concentrated and the crude residue obtained is filtered. By recrystallization twice from a mixture of tetrahydrofuran and methanol, pure 8- (1-hydroxyethyl) -1-methyl-6-pheny1-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine dipicrate is obtained as yellow rods with a melting point of 143-145 °.

Example 24

A solution of 56.4 g (0.20 mol) 1,3-dihydro-7-ethyl-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2.0 l of tetrahydrofuran containing 4 mol of monomethylamine is cooled in an ice bath. 33.0 ml (0.30 mol) of titanium tetrachloride in 350 ml of benzene are added to the reaction mixture. The reaction mixture is stirred for 3 days at room temperature.

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The txtane tetrachloride is destroyed with 100 ml of water. The inorganic salts are removed by filtration. The filtrate is concentrated to dryness in vacuo. The residue is distributed between methylene chloride and water. The methylene chloride phase is dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue from acetonitrile gives 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine as light yellow prisms with a melting point of 172-174 °.

An analytical sample is recrystallized from acetonitrile.

172-174 ⁽

sates and delivers light yellow prisms from the melting point, or similar

8.6 g (0.125 M) sodium nitrite are added for 1/2 hour in three portions to a solution of 29.5 g (0.1 M) 7-ethyl-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine put in 100 ml of glacial acetic acid. The reaction mixture is stirred for a further 1/2 hour at room temperature, then with ice water diluted and extracted with methylene chloride. The extracts are washed with water and aqueous bicarbonate solution, dried over sodium sulfate, evaporated and give crude 7-ethyl-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine as a yellow OeI.

This product is dissolved in 100 ml of dimethylformamide. The solution becomes a mixture of 100 ml of dimethylformamide 35 ml of nitromethane and 9.9 g of potassium t-butoxide, which was stirred for 1/2 hour at room temperature, were added. When the addition is complete, the reaction mixture is left to stand for 1 hour at room temperature and then for 30 minutes on the steam bath touched. The cooled solution is acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water, dried and evaporated. The residue is dissolved in 50 ml of ethanol, whereupon the solution is brought to crystallization overnight in the refrigerator with inoculation. The yellow crystals are collected and taken out

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Recrystallized ethanol, using!, S-dihydro-V-ethyl-S- (2-f luophenyl) ^ -nitromethylene ^ H-1,4-benzodiazepine of melting point 138-140 °. The seed crystals are obtained by chromatography of the crude product on a 40-fold amount of silica gel obtained using a 5% solution of ethyl acetate in methylene chloride as a flow agent. An analytical sample is made crystallized from ether / hexane and has a melting point of 138-141 °.

2.6 g _/ 3-dihydro-7-ethyl-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine in 30 ml of ethanol are hydrogenated with 1 teaspoon of Raney nickel for 4 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in ether and the amine is extracted with 10% aqueous acetic acid. The extracts are washed with ether and made alkaline with ammonia. The precipitated amine is extracted with methylene chloride. The extracts are dried, evaporated and give crude 2-aminomethyl-2,3-dihydro-7-ethyl-5- (2-fluorophenyl) -1H-1,4-benzodiazepine. This product is dissolved in 50 ml of xylene. After adding 3 ml of triethyiorthoacetate, the solution is refluxed for 2 hours. The residue obtained after evaporation under reduced pressure is chromatographed on 50 g of silica gel, a 20% solution of methanol in methylene chloride being used as the mobile phase. The homogeneous fractions are combined and evaporated to give 3a, 4-dihydro-8-ethyl-6- (2-fluorophenyl) -1-methyl-OH-imidazo [1,5-a] - [1,4] benzodiazepine. This material is dissolved in 50 ml of toluene. After adding 5 g of activated manganese dioxide, the solution is refluxed for 1 hour. The inorganic material is removed by filtration and the filtrate is evaporated. The residue is dissolved in ether and treated with ethanolic hydrochloric acid and acetone. The crystalline dihydrochloride (melting point 248-255 °) is collected and converted back into the base by partitioning between methylene chloride and aqueous ammonia. The methylene chloride phase is dried and evaporated. By crystallization of the residue

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Ether / hexane gives 8-ethyl-6- (2-fluorophenyl) -l-methyl ^ H-imidazo [l, 5-a] [l, 4] benzodiazepine from melting point 152-154 °.

Example 25

27.6 g (0.4 M) sodium nitrite are used for a period of 30 minutes in portions to a solution of 90.45 g (0.3 M) 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 400 ml of glacial acetic acid are added. After the addition has ended, the reaction mixture is stirred for 1 hour at room temperature, with 1 Diluted liters of water and extracted with methylene chloride. The extracts are made twice with water and then with 10% aqueous Washed sodium carbonate solution. The solution is dried and evaporated to give crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine as a yellow OeI.

This product is dissolved in 300 ml of dimethylformamide to a mixture of 150 ml of dimethyl malonate, 40.4 g of potassium butoxide and 500 ml of dimethylformamide, which was previously stirred for 10 minutes at room temperature, added. mixture is stirred overnight at room temperature under nitrogen, acidified by adding 50 ml of glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water and aqueous sodium carbonate solution, dried over sodium sulfate and evaporated. Crystallization of the residue from ethanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl-2H-1,4-benzodiazepine as colorless crystals with a melting point of 170-172 ° _o For analytical purposes Purpose, the product is recrystallized from methylene chloride / ethanol and shows an unchanged melting point.

A mixture of 20 g (0.05 M) 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine, 400 ml of methanol and 3.3 g (0.059 M) of potassium hydroxide are refluxed under nitrogen for 5 hours. After removal

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of the bulk of the solvent, the residue gradually becomes
diluted with water, whereupon the precipitated crystals are collected, washed with water and dried. 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dirnethoxycarbonylmethylene) -2H-1,4-benzodiazepine with a melting point of 158-160 is obtained.

For analytical purposes, the product is recrystallized from methylene chloride / hexane and has a melting point of 161-162 °.

8.8 g (0.125 M) sodium nitrite are added to a solution of 28 g (0.08 M) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxycarbonylmethylene) -2H-l, 4-benzodiazepine given in 250 ml of glacial acetic acid. The mixture is stirred for 10 minutes at room temperature and then diluted with 250 ml of water. The crystalline
The product is filtered off, washed with water, methanol and ether and dried. 7-Chloro-5- (2-fluorophenyl) -a-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is obtained as yellow crystals with a melting point of 238 ° -241 ° (decomposition).

11.25 g (0.03 M) 7-chloro-5- (2-fluorophenyl) -cc-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester are in a mixture of 750 ml tetrahydrofuran and 500 ml of methanol
Hydrogenated with Raney nickel at atmospheric pressure. The catalyst
is filtered off and the filtrate is evaporated. The residue is dissolved in 100 ml of methanol and 11 ml of triethyl orthoacetate, whereupon 5 ml of ethanolic hydrochloric acid (5%) are added.
The mixture is refluxed for 10 minutes and then evaporated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The methylene chloride solution is dried and evaporated. The residue
is chromatographed on 300 g of silica gel, methylene chloride / ethyl acetate (1: 3) being used as the eluent. The clear ones
Fractions are combined and evaporated and the residue is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester with a melting point of 162-164 °. An analytical sample is recrystallized from ethyl acetate / hexane.

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Example 26

11.25 g (0.03 M) 7-chloro-5- (2-fluorophenyl) -a-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is heated in a mixture of 750 ml tetrahydrofuran and 500 ml of methanol dissolved. After adding 20 g of Raney nickel, the reaction mixture is hydrogenated for 4 hours at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated, with azeotropic evaporation with toluene at the end. The residue is dissolved in 100 ml of methanol. After adding 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrochloric acid (5%), the reaction mixture is refluxed for 10 minutes and then evaporated. The residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The methylene chloride phase is separated off, dried and evaporated. The residue is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -4H-imidazo [l, 5-a] [l _f 4] benzodiazepine-3-carboxylic acid methyl ester, which after recrystallization from methylene chloride / ether / Haxane shows the melting point 179-181 °.

Example 27

A mixture of 7.7 g (0.02 M) 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 2.24 g (0.04 M) potassium hydroxide, 200 ml methanol and 6 ml water are heated to reflux for 3 1/2 hours, whereupon the solvent is partially evaporated. The residue is acidified with glacial acetic acid and heated with Water diluted. The precipitated crystals are collected and, after cooling in ice water, dried. 8-Chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid is obtained. For analytical purposes, the product is recrystallized from methylene chloride / methanol / ethyl acetate and shows the melting point 271-274 ° (dec.).

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3ϋ

Example 28

A suspension of 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl} -l-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 25 ml of 2-propanol is warmed on the steam bath and treated with 2.2 ml of 5N potassium hydroxide solution. As soon as the The solution is complete, the potassium salt is crystallized out by cooling in ice water. It is collected with 2-propanol and ether washed, dried in a high vacuum at 90 and yields 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid potassium salt hydrate as colorless crystals with a melting point of 245-255 °.

Example 29

A mixture of 1.48 g (0.004 M) S-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 0.5 g (0.009 M) potassium hydroxide, 50 ml methanol and 2 ml water is refluxed for 3 hours under a nitrogen atmosphere heated. The methanol is partially concentrated, whereupon the residue is acidified with glacial acetic acid and heated with water is diluted. The precipitated crystals are collected after cooling in ice water and dried in vacuo. You get 8-Chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid of melting point 245-247 ° (dec.).

Example 30

A solution of 7.7 g (0.02 M) of methyl 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate in 100 ml of tetrahydrofuran is added at 0-5 ° to a solution of 2 g (0.05 M) of lithium aluminum hydride in 100 ml Aether given. After the addition has ended, the reaction mixture is stirred for 15 minutes without cooling and then by addition hydrolyzed by 15 ml of water. The inorganic material is removed by filtration and washed with methylene chloride.

609815/1301

The filtrate is dried and evaporated. By crystallization the residue is obtained from methylene chloride / ether / hexane one 8-chloro-6- (2-fluorophenyl) -S-hydroxymethyl-1-methyl- ^ H-imidazo [1,5-a] [1,4] benzodiazepine, which is recrystallized from ethyl acetate / methanol for analytical purposes and the Shows melting point 233-235 °.

Example 31

A mixture of 4 g of 8-chloro-6- (2-fluorophenyl) -3-hydroxymethy1-1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine, 200 ml of methylene chloride and 20 g of activated manganese dioxide are stirred for 1 hour at room temperature. The manganese dioxide will durch.Filtrieren removed and washed well with methylene chloride. The filtrate is evaporated and the residue becomes crystallized from methylene chloride / ether / hexane and yields 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxaldehyde, which, after recrystallization from methylene chloride / ethyl acetate / hexane, has a melting point of ISO-192 ° shows.

Example 32

A solution of 0.71 g (2 mt-Iol) of 8-chloro-6- (2-fluorophenyl) -S-hydroxymethyl-1-methyl ^ H -imidazo [1,5-a] [1,4] benzodiazepine in 20 ml of pyridine is treated with 2 ml of acetic anhydride. After standing overnight, the solvent is reduced under reduced pressure Evaporated pressure. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and evaporated. The residue does not crystallize and is purified by chromatography on 30 g of silica gel, whereby methylene chloride / ethyl acetate (1: 3) is used as a flow agent. The homogeneous fractions are combined and evaporated to give S-acetoxymethyl-e-chloro-e- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, which does not crystallize and is characterized by spectroscopy.

6098 157 130 1

Example 33

26 g of potassium t-butoxide (0.232 M) become a mixture of 300 ml of dimethylformamide and 50 ml (0.44 M) of dimethyl malonate. After stirring for 10 minutes under nitrogen, a Solution of 66 g (0.209 M) 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide in 100 ml of dimethylformamide added over a period of 10 minutes. The mixture will then slowly heated on the steam bath and held at 65 ° for 10 minutes. After cooling to room temperature, 40 ml Glacial acetic acid and then 1 liter of water over a period of 30 minutes, with occasional scratching. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution will be over Dried sodium sulfate and concentrated to a small volume. By adding hexane, crystalline 7-chloro-1,3-dihydro-2- (Dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide with a melting point of 188-190 °. An analytical sample is made recrystallized from methylene chloride / hexane and shows the Melting point 194-195 °.

a) The mixture of 40.8 g (0.1 M) 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -S-phenyl ^ H-l ^ -benzodiazepine ^ -oxide, 250 ml of methanol, 250 ml of tetrahydrofuran and 1 teaspoon of Raney nickel are hydrogenated for 5 hours at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. By crystallization of the residue Methylene chloride / 2-propanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine as colorless crystals with a melting point of 160-163 °. For analytical purposes, the product is recrystallized from 2-propanol and shows the Melting point 165-166 °.

On some occasions a second crystal modification with a melting point of 138-140 ° was obtained.

b) 4 ml of phosphorus trichloride become a solution of 4 g (0.01 M) 7-chloro-1,3-dihydro-2- (2-dimethoxymalonylidene) -5-r

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- S3 -

phenyl-2H-l, 4-benzodiazepine-4-oxide given in 100 ml of methylene chloride, - After leaving to stand overnight, the solution is with washed a 10% aqueous sodium carbonate solution. the The methylene chloride phase is dried and evaporated. By Crystallization of the residue from 2-propanol and recrystallization 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine is obtained from methylene chloride / 2-propanol from a melting point of 165-166 °.

A mixture of 115 g (0.3 M) 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine, 1.5 l of methanol and 14.4 g (0.36 M) sodium hydroxide are added under nitrogen heated to reflux for 5 hours. The cold reaction mixture is gradually increased with 2.5 1 while cooling with ice Water diluted. The precipitated crystals are collected, washed with water, dried in vacuo at 60 and delivered 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine as a whitish product with a melting point of 167-170 °. An analytical sample is recrystallized from ether and shows the melting point 171-] 73 ° «

2.8 g (0.04 M) sodium nitrite is added to a solution of 8 g (0.025 M) 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine put in 100 ml of glacial acetic acid. The reaction mixture is under nitrogen for 10 minutes touched. A product crystallizes out after a few minutes. After dilution with 100 ml of water, the precipitated Crystals collected, washed with water, dried, recrystallized from tetrahydrofuran / methanol and yield 7-chloroct-hydroxyimino-5-phenyl-3H-1, 4-benzodiazepine-2-acetic acid methyl ester as yellow crystals with a melting point of 235-237 ° (Decomposition).

3.6 g (0.01 M) 7-chloro-cc-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester are heated in a mixture of 200 ml of tetrahydrofuran and 100 ml of methanol solved. After adding 1 teaspoon of Raney nickel, the

6098 15/1301

Reaction mixture until the hydrogen uptake has ended (1st Hour and 10 minutes) hydrogenated. The catalyst is removed by filtration and the filtrate is evaporated, whereby is finally evaporated azeotropically with toluene. The residue is dissolved in 20 ml of methanol. After adding 3 ml of triethyl orthoacetate and 0.3 ml of ethanolic hydrochloric acid (5%), the solution is heated to reflux for 5 minutes. The one after evaporation the residue obtained from the reaction mixture is used Distributed methylene chloride and aqueous sodium carbonate solution. The organic phase is separated off, dried and evaporated. Crystallization of the residue from ether gives 8-chloro-l-methyl-6-phenyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3- methyl carboxylate which, after recrystallization from methylene chloride / ether / hexane, has a melting point of 254-256.

Example 34

A mixture of 7.3 g (0.02 M) S-chloro-l-methyl-o-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 2.24 g (0.04 M) potassium hydroxide, 200 ml methanol and G ml Water is refluxed for 4 hours. The methanol is partially removed under reduced pressure. The residue is acidified with glacial acetic acid and crystallized by adding water. The crystals will be collected, washed with water, dried and give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid as a whitish product. For analysis purposes, the product is recrystallized from ethyl acetate and shows the Melting point 270-273 ° (decomp.).

Example 35

A solution of 0.73 g (2 mmol) of 8-chloro-l-methyl-ö-phenyl-4H-imidazo [l, 5-a] [1 ^ benzodiazepine-S-carboxylic acid methyl ester in 50 ml of tetrahydrofuran is added to a suspension, cooled to -10, of 0.3 g (7.5 mmol) of lithium aluminum hydride in 20 ml Given tetrahydrofuran.

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After the addition has ended, the reaction mixture is stirred for 30 minutes without cooling and then hydrolyzed by adding 2 r.il water. The inorganic material is filtered off and the filtrate is dried and evaporated. Crystallization of the residue from methylene chloride / ether / hexane gives e-chloro-S-hydroxymethyl-1-methyl-ephenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 252-255 °.

Example 36

A suspension of 1.5 g of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 10 ml of mineral oil is heated to 230 ° for 5 minutes. The reaction mixture • is distributed between IN hydrochloric acid and ether. the aqueous phase is made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated, and the residue is chromatographed on 60 g of silica gel, a 25% solution of methylene chloride in ethyl acetate is used as the eluent. The less polar one 8-chloro-6- (2-fluorophenyl) -6H-imidazo [1,5-a] [1,4] benzodiazepine crystallizes from ethyl acetate and gives colorless crystals with a melting point of 195-196 °.

The more polar component is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine from a melting point of 150-151 °.

Example 37

A mixture of 3 g e-chloro-S-hydroxymethyl-l-methyl-ephenyl-4H-imidazo [l, 5-a] [1,4] benzodiazepine, 300 ml of methylene chloride and 15 g of activated manganese dioxide are stirred for 1 hour at room temperature. The manganese dioxide is filtered off and washed with methylene chloride. The filtrate is evaporated and the residue is made from methylene chloride / ether / hexane crystallizes and gives 8-chloro-l-methyl-6-phenyl-4H-imidazo-

609815/13 01

[1,5-a] [1,4] benzodiazepine-3-carboxaldehyde of melting point

218-220 °.

Example 38

0.74 g (2 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo- [1,5-a] [l-benzodiazepine-S-carboxylic acid methyl ester are in 30 ml of methanolic ammonia for 18 hours in a closed Container heated to 120 °. The solvent is evaporated and the residue is made up of methylene chloride / Ethanol crystallizes and gives 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide as colorless Crystals with a melting point of 335-340.

Example 39

A mixture of 0.74 g (2 mmol) of S-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-S-carboxylic acid methyl ester and 20 ml of ethanol containing 25% methylamine are heated to 120 in a closed container for 18 hours. The solvent is evaporated and the residue is crystallized from methylene chloride / ethanol and yields 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-N-methyl-carboxamide from a melting point of 260-263 °. An analytical sample is recrystallized from tetrahydrofuran / ethanol.

Example 40

2 g of zinc dust are converted into a solution of 1.83 g (5 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester given in 50 ml of methylene chloride and 10 ml of glacial acetic acid. The reaction mixture is for 2 hours stirred at room temperature. The inorganic material is filtered off and the filtrate is washed with dilute aqueous Ammonia washed. The methylene chloride solution is dried and evaporated. By crystallization of the residue Methylene chloride / ethyl acetate / ether gives 8-chloro-5,6- ·

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methyl dihydro-1-methyl-6-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate as colorless crystals with a melting point of 233-235 °. An analytical sample is made from ethyl acetate / Methylene chloride / methanol recrystallizes and has a melting point of 234-236 °.

Example 41

A mixture of 7.7 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid diethyl ester _/ 100 ml of isobutanol and 20 ml of hydrazine is refluxed for 1 hour. The crude product obtained after evaporation is chromatographed on 250 g of silica gel, a 5% solution of ethanol in methylene chloride being used as the eluent. The clear fractions are combined and evaporated. Crystallization of the residue from methylene chloride / ether gives 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid hydrazide as a colorless one Crystals with a melting point of 235-237 °,

Example 42

A mixture of 7.4 g of ephenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 20 ml of hydrazine and 200 ml of isobutanol are heated to reflux for 3 hours. The after evaporation of the The residue obtained in the reaction mixture under reduced pressure is crystallized from ethanol / ether and yields e-chloro-S ^ -dihydro-1-methyl-δ-pheny1-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylic acid hydrazide from melting point 225-230. An analytical sample is recrystallized from ethyl acetate / methanol and shows the melting point 228-230 °.

Example 43

A solution of 0.73 g (2 mmol) of 8-chloro-1-methy1-6-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester

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Si

in 20 ml of dry dimethylformamide is cooled to -30 ° with stirring and under nitrogen. After adding 0.25 g (2.2 mmol) Potassium t-butoxide and stirring for a further 5 minutes are 0.3 g (2.1 mmol) methyl iodide added. The reaction mixture is brought to room temperature within 1 hour and then partitioned between saturated aqueous bicarbonate solution and methylene chloride. The methylene chloride phase is washed with water, dried and evaporated. By crystallizing the residue 8-chloro-1,4-dimethyl-6-phenyl-4H-imidazo- [1,5-a] [1,4] methyl benzodiazepine-3-carboxylate is obtained from ether as colorless crystals with a melting point of 217-221 °. An analytical sample is recrystallized from ethyl acetate / hexane and shows the Melting point 220-222 °.

Example 44

0.25 g (2.2 mmol) of potassium t-butoxide are added to a solution, cooled to -30 °, of 0.74 g (2 mmol) of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1 , 5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester given in 20 ml of dimethylformamide. After 5 minutes i 0.33 g (2.26 mmol) of methyl iodide are added while stirring under nitrogen. The reaction mixture is on for 30 minutes Brought to room temperature. Then partition between aqueous bicarbonate and methylene chloride. The organic phase is with Washed water, dried and evaporated. The residue is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -4-methyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3-carboxylic acid methyl ester, which after recrystallization from Ethyl acetate / hexane shows the melting point 190-191 °.

Example 45

3.4 g (0.01 M) 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] - [1,4] benzodiazepine-3-carboxaldehyde is partially dissolved by heating in 200 ml of ethanol. After adding 1.05 g (0.015 M) Hydroxylamine hydrochloride and 4 ml of triethylamine, the reaction mixture is heated on the steam bath until the solution is full.

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is constantly. The solution is partially evaporated and the product is crystallized by dilution with water. the Crystals are collected, washed with ethanol and ether, dried and yield S-chloro-1-methyl-e-phenyl ^ H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxaldoxime of melting point 280-282 ° (decomp.). An analytical sample is recrystallized from ethanol / tetrahydrofuran.

Example 46

2.1 g of 8-chloro-1-methyl-6-pheny1-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxaldoxime are dissolved by heating in 100 ml of ethanol and 100 ml of tetrahydrofuran. The solution will be hydrogenated for 3 hours at atmospheric pressure in the presence of 1 teaspoon of Raney nickel. The catalyst is filtered off, and the filtrate is evaporated. Crystallization of the residue from 2-propanol / ether gives 3-aminomethyl-8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. For analysis purposes, this product is recrystallized from ethanol / ether and has a melting point of 217-219 °.

Example 47

0.3 g (0.00082 M) of 8-amino-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine-isopropanol are added to 5 ml of acetic anhydride given, whereupon the reaction mixture is heated on the steam bath for 1 hour and then evaporated to dryness. The residue is dissolved in 25 ml of dichloromethane, washed with 15 ml of 5% potassium carbonate solution, dried over anhydrous sodium sulfate and used for Evaporated dry. Twice crystallization from a mixture of methanol / ethyl acetate gives 8-acetamido-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as white rods with a melting point of 326-331 °.

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- 190 ~

Example 48

A solution of 0.8 g (0.0024 M) S-acetamido-δ- (2-fluorophenyl) -l-methyl-4H-imida2o [1,5-a] [1,4] benzodiazepine in 10 ml of dry Ν, Ν-dimethylformamide is 0.13 g under nitrogen (0.003 M) of a 55% sodium hydride dispersion in mineral oil treated, whereupon after 30 minutes the reaction mixture in a Ice bath is cooled. The stirred reaction mixture is mixed with 0.43 g (0.003 M) methyl iodide, then at 18 hours Let stand room temperature and then poured onto water. Filtration gives a crude product, which is made of a Mixture of ethyl acetate and ether is recrystallized. 6- (2-Fluorophenyl) -1-methyl-8- (N-methylacetamido) -4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained as whitish prisms with a melting point of 217-223 °.

Example 49

A solution of 0.3 g (0.000828 M) 6- (2-fluorophenyl) -lmethyl-8- (N-methylacetamido) -4H-imidazo [1,5-a] [1,4] benzodiazepine in 10 ml of methanol is treated with 3 ml of concentrated hydrochloric acid and heated to reflux for 1 hour. The solution is made basic with ammonium hydroxide and then partitioned between ml of dichloromethane and 50 ml of water. The organic Phase is dried over anhydrous sodium sulfate and evaporated to dryness. The OeI obtained as a residue is in 10 ml of dichloromethane dissolved. The solution is filtered through Florisil, whereby ether, ethyl acetate and finally ethyl acetate, containing 5% methanol, can be used as eluent. This last mixture is evaporated and out of a mixture brought to crystallization by ethyl acetate and ether. 6- (2-fluorophenyl) -1-methyl-S-methylamino ^ H-imidazo [1,5-a] [1,4] benzodiazepine is obtained as whitish prisms with a melting point of 255-259 °.

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- ΙΟΙ -

Example 50

A solution of 0.3 g (0.00082 M) 8-amino-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-isopropanol in 0.5 ml of sulfuric acid is treated with 4 g of ice and then with 0.2 g (0.0029 M) of sodium nitrite. After 5 minutes it will the reaction mixture added to a freshly prepared solution, which was prepared as follows: 1 g (0.007625 M) Copper sulfate in 10 ml of water is added to 1 g (0.00794 M) sodium sulfite in 5 ml of water, whereupon 8 g (0.116 M) Add sodium nitrite in 40 ml of water. After 15 minutes, the reaction mixture is heated to 35 ° for 5 minutes with 10% strength Potassium carbonate solution made basic and with 100 ml dichloromethane extracted. The organic phases are combined, dried over anhydrous sodium sulfate and placed on a silica gel thick layer plate applied. This is developed with a mixture of ethyl acetate and ethanol (10: 1), and the stain with an Rf value of 0.5 it is scratched off. By crystallization from methanol and ümkristaliisierung from a mixture of Dichloromethane and ether are obtained (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-nitrophenyl] methanone from melting point 188-192 °.

Example 51

A solution of 0.5 g (0.00137 M) 8-amino-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine isopropanol in 20 ml of formic acid and 5 ml (0.062 M) 37% formaldehyde is heated on the steam bath for 3 hours and then concentrated to dryness. The residue is dissolved in 50 ml of dichloromethane. The solution is mixed with 15 ml of 10% strength potassium carbonate solution washed, dried over anhydrous sodium sulfate and concentrated. The oil obtained as a residue is applied to 2 silica gel thin-layer plates and developed with a mixture of ethyl acetate and ethanol (7: 1). That Product with Rf value 0.4 is scraped off, washed with methanol, filtered and evaporated. The OeI obtained is in

609815/1301

Dissolved ether, and the solution with 5 ml of a 10% ethanol Solution of picric acid added. The precipitate is filtered and from a mixture of tetrahydrofuran and Isopropanol crystallizes, with (2-fluorophenyl) - [2- (2-methy1-5-dimethylaminomethyl-1-imidazolyl) -5-dimethylaminophenyl] methanone dipicrate obtained as yellow prisms with a melting point of 228-230 °.

Example 52

a) A solution of 3 g (0.00920 M) 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 50 ml of water and 0.5 ml (0.4092 M) concentrated sulfuric acid is with 1.5 g (0.0217 M) sodium nitrite treated. After 18 hours, a further 0.5 ml of sulfuric acid and a further 1.5 g of sodium nitrite are added added, whereupon after 10 minutes the reaction mixture is made basic with ION sodium hydroxide. The reaction mixture is extracted with 75 ml of dichloromethane, over anhydrous Dried sodium sulfate and evaporated to dryness. By crystallization of the residue from a mixture of Acetate and ether are obtained (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl] methanone as white prisms with a melting point of 165-168 °.

b) A solution of 1 g (0.00240 M) 5-aminomethyl-1- [4-chloro-2- (2-fluorobenzoylphenyl] -2-methylimidazole dihydrochloride is dissolved in 20 ml of water. 1 g (0.0145 M) sodium nitrite is slowly added to the solution in an ice bath while stirring. To The reaction mixture is made basic with ION sodium hydroxide for 3 hours and extracted with 50 ml of dichloromethane. the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from ethyl acetate gives (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl] methanone as white prisms with the melting point and mixed melting point a sample of the product obtained according to a) from 163-166.

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- IC / 5 -

To a mixture of 0.1 g (0.000273 M) 8-amino-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine isopropanol and 1 ml of concentrated hydrochloric acid is added to 5 ml of water. The reaction mixture is cooled in an ice bath and 0.15 g (0.00217 M) of sodium nitrite are slowly added while stirring. After 1 hour, the reaction mixture increases to a level 70 ° -mt solution of 0.2 g (0.00202 M) copper (i) chloride in

-> r poured. After 18 hours, sodium hydroxide is used alIt and extracted with twice 50 ml dichloromethane, Colds are dried over anhydrous sodium sulphate and evaporated to dryness. The residue is on a Silica gel thick layer plate developed with a mixture of ethyl acetate and methanol (10: 1). The product of the Rf value 0.7 is scraped off, stirred with methanol and filtered. By evaporation and crystallization of the crude product from a mixture from ethyl acetate and ether one obtains (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-l-imidazolyl) -5-chlorophenyl] - methanone as white prisms with a melting point and a mixed melting point with an authentic sample of 159-166 °.

Example 53

A solution of 0.5 g (0.00145 M) (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl] methanone in 25 ml of dichloromethane is treated with 0.15 ml (0.00155 M) of phosphorus tribromide in an ice bath. The reaction mixture is Left to stand for 1 hour at room temperature and then poured onto 50 ml of liquid ammonia. After the ammonia has evaporated the reaction mixture is distributed between 50 ml of dichloromethane and water. The organic phase is separated over dried anhydrous sodium sulfate and concentrated. The residue is applied to two silica gel thick layer plates and developed with a mixture of ethyl acetate / 10% methanol.

The compound with the Rf value 0.6 is made by "the plates scraped off, stirred with methanol and filtered. The solution will be

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_. - 104 -

treated with 0.1 g (0.000962 M) maleic acid and evaporated. The salt obtained as residue is crystallized from a mixture of isopropanol and ether and gives 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate as white prisms from the melting point and mixed melting point with an authentic sample of 112-115 (melting point of the solvated product). The base is made by partitioning the salt between dichloromethane and water, adjusting the pH, phase separation and concentration of the organic phase released. Obtained by crystallization of the product from ether white prisms of melting point and mixed melting point with an authentic sample of 154-157.

Example 54

A solution of 1.7 g (0.005 M) 8-chloro-3-hydroxymethyl-imethyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in 5 ml of thionyl chloride is stirred for 30 minutes at room temperature. Crystallized by adding ethyl acetate and ether the hydrochloride of S-chloro-S-chloromethyl-1-methyl-e-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine the end. The crystals are collected and washed between methylene chloride and saturated aqueous Sodium bicarbonate solution distributed. The organic phase is dried and evaporated. By crystallizing the residue 8-chloro-3-chloromethyl-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained from methylene chloride / ether which in 50 ml of methanol containing 0.5 g of sodium methoxide / is heated to reflux for 10 minutes. The methanol is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried and evaporated.

By chromatography of this crude material on 30 g of silica gel, using methylene chloride / ethyl acetate (1: 3) as the eluent is used, after crystallization from ethyl acetate / hexane, e-chloro-S-methoxymethyl-1-methyl-ö-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained as colorless crystals from

Melting point 163-165 °. _e " _981S , ₁₃₀₁ Example 55

2 ml of triethylamine and 0.5 g of methoxyamine hydrochloride are used to a warm solution of 0.67 g (0.002 M) 8-chloro-l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde given in 40 ml of ethanol. The reaction mixture is left to stand for 30 minutes. The solvent is partially evaporated and the product is crystallized out by dilution with water. The crystals are collected, dried and provide 8-chloro-3- (N-methoxyiminomethyl) -l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine. An analytical sample is recrystallized from ether and has a melting point of 193-195 °.

Example 56

4 ml of pyrrolidine is added to a solution of the acid chloride prepared from 1.85 g of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylic acid and 1.25 g of phosphorus pentachloride, placed in 250 ml of methylene chloride. Afterward 100 ml of 10% aqueous sodium carbonate solution are added and the two-phase mixture is stirred for 1 hour at room temperature. The organic phase is separated off, dried and evaporated. By crystallizing the residue 1- [8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepin-3-oyl] pyrrolidine is obtained from 2-propanol / ether as a colorless product which, after recrystallization from ethyl acetate / hexane, has a melting point of 220-221 °.

■ Example 57

10 ml of 2,2-dimethylhydrazine become a solution of the acid chloride, which is obtained as described in Example 56 from X, 85 g-8-chloro-δ- (2-fluorophenyl) -l-methyl- ^ H-imidazo [1.5 -a] - [l, 4] benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride was added to 250 ml of methylene chloride. After adding 100 ml of 10% aqueous sodium carbonate solution,

B098-1 B / 1301

the reaction mixture was stirred for 30 minutes at room temperature. The organic phase is separated off, dried and evaporated. Crystallization of the residue from ether / ethanol gives 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid-2,2 -dimethylhydrazide as a colorless product. An analytical sample is chromatographed on a 30-fold amount of silica gel, wherein a 10% solution of ethanol in methylene chloride is used as a flow agent. After crystallization from methylene chloride / In ethyl acetate / hexane, the product has a melting point of 238-240 °.

Example 58

A mixture of 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -lrmethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 1, ^c diphenylphosphorazide , 30 ml of dimethylformamide and 2 ml of triamine is stirred for 15 minutes at room temperature. Addition of 6 ml of methanol, the reaction mixture is heated to reflux for <30 minutes. The solvent was removed under reduced pressure, with final azeotropic evaporation with xylene. Crystallization of the residue from ethyl acetate gives 8-chloro-6- (2-fluorophenyl) -3- (methoxycarbonylamino) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, which after recrystallization from methylene chloride / methanol / ethyl acetate shows the melting point 270-275 °. An analytical sample is recrystallized from tetrahydrofuran / ethanol shows the melting point 272-275 ° (decomp.) "

Example 59

A mixture of 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 1.5 g diphenyl phosphorazide, 10 ml dimethylformamide, 25 ml Toluene and 2 ml of triethylamine are stirred for 10 minutes at room temperature. After adding 10 ml of benzyl alcohol the reaction mixture is refluxed for 30 minutes

8098 15/1301

heats. The after evaporation of the solvent under reduced The residue obtained under pressure is crystallized from ether and gives 3- (benzyloxycarbonylamino) -8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine from melting point 250-253. An analytical sample is recrystallized from methylene chloride / methanol / ethyl acetate and shows the melting point 253-255 °.

Example 6O

1.8 g (2.5 mmol) of sodium nitrite are added for 5 minutes in portions to a solution of 3.7 g (10 mmol) of 8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3- carboxylic acid hydrazide added to 35 ml of glacial acetic acid. After stirring for 30 minutes at room temperature, the azide is replaced by Adding water and ice precipitated. The solids are collected and dissolved in methylene chloride. The solution is with Water, sodium carbonate solution and ice washed, dried and evaporated o The residue is in a mixture of Dissolved 100 ml of dimethylformamide and 25 ml of methanol. The solution is refluxed for 20 minutes (temperature approx. 103) after which the solvents are removed under reduced pressure. The residue is made from methanol / ethyl acetate crystallizes and gives 8-chloro-3-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 255-258 ° (decomp.). An analytical sample is made from tetrahydrofuran / Recrystallizes ethanol and shows the same melting point.

Example 61

2.06 g (5 mmoles) of e-chloro-S-methoxycarbonylamino-1-methyl-5-nitroso-6-phenyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine are dissolved by heating in a mixture of 200 ml of tetrahydrofuran and 100 ml of methanol. The 'reaction mixture becomes after adding 2 teaspoons of Raney nickel during

809815/1301

Hydrogenated for 1 hour at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. Crystallization of the residue from methanol gives 8-chloro-5,6-dihydro-3- (methoxycarbonylamino) -l-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 280-290 ° (decomp.). An analytical sample is made recrystallized from ethyl acetate / methanol.

Example 62

A mixture of 9.75 g (0.03 M) 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 200 ml of methylene chloride and 12 g (0.07 M) of m-chloroperbenzoic acid stirred for 1 1/2 hours. The solution is then extracted three times with 150 ml of IN hydrochloric acid. The extracts are made with Washed ether, made alkaline with ammonia and extracted with methylene chloride. The methylene chloride extracts are dried and evaporated. The residue is crystallized from ethyl acetate and chromatographed on 100 g of silica gel, a 5% solution of ethanol in methylene chloride is used as a flow agent, further purified. The clear ones Fractions are combined and evaporated. Crystallization of the residue from ethyl acetate / ether is obtained 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] -benzodiazepine-5-oxide as colorless crystals with a melting point of 245-246 ° (decomp.).

Example 63

A solution of 4 g of 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide in 100 ml · acetic anhydride is heated on the steam bath for 24 hours. The reaction mixture is evaporated under reduced pressure and finally evaporated azeotropically with xylene. The residue is chromatographed on 80 g of silica gel, using a 20% solution of methylene chloride in ethyl acetate as the eluent ' is used. By crystallizing the clear fractions

60981B / 1301

4-acetoxy-S-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained from methylene chloride / ether as colorless crystals with a melting point of 201-202.

Example 64

0.5 g (1.3 mmol) of 4-acetoxy-8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4JbBnZOdIaZePXn are added to 40 ml of methanol containing 4 mmol of sodium methoxide. After half an hour Stirring under nitrogen at room temperature, the solvent is evaporated under reduced pressure. The residue is dissolved in water, and the solution is acidified with acetic acid. The precipitated crystals are collected and in Dissolved methylene chloride. The solution is dried and evaporated. The residue is crystallized from methylene chloride / ether and provides 8-chloro-6- (2-fluorophenyl) -4-hydroxy-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 185-186 °.

Example 65

A mixture of 9.75 g (0.03 M) 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 18 g (0.105 M) m-chlorobenzoic acid and 200 ml of methylene chloride stirred overnight at room temperature. Dilute NaGh with 500 ml of ether, the reaction mixture is extracted four times with 75 ml of IN hydrochloric acid. The extracts are washed with ether, Made alkaline with ammonia and extracted with methylene chloride. The extracts are dried and evaporated. Crystallization from ethyl acetate gives 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide.

The aqueous phase is evaporated to dryness under reduced pressure. The residue is well with methylene chloride containing 20% ethanol, washed. The combined washing liquids are evaporated to give crude 2,5-dioxide, which

80981B / 1301

25A0522

is chromatographed on 40 g of silica gel, with a 50% Solution of methanol in methylene chloride is used as an eluent. After eluting the less polar 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-2-oxide from melting point 179-181 ° (decomp.; After crystallization from ethyl acetate / methanol) the pure fractions of the 2,5-Dioxyds combined and evaporated. Crystallization of the residue from ethyl acetate gives 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-2,5-dioxide as whitish crystals with a melting point of 225-230 (decomp.). An analytical sample is recrystallized from methanol / ethyl acetate.

Example 66

A solution of 1 g of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [l _r 5-a] [l, 4] benzodiazepine-2,5-dioxide in 10 ml of acetic anhydride is used for 15 Heated for minutes on the steam bath. The reaction mixture is evaporated under reduced pressure and the residue is crystallized from ethyl acetate / ether. 1-Acetoxymethyl-S-chloro-δ- (2-fluorophenyl) -4H-imidazo- [1,5-a] [1,4] benzodiazepine-5-oxide is obtained as crystals with a melting point of 203-205 °. For analytical purposes, the product is recrystallized from ethyl acetate.

Example 67

A mixture of 1 g of l-acetoxymethyl-e-chloro-e- (2-fluorophenyl) -4H-imidazo [l _r 5-a] [1,4] benzodiazepine-5-oxide, 30 ml of methylene chloride and 3 ml of phosphorus trichloride is used left to stand for 24 hours at room temperature. The residue obtained after evaporation of the reaction mixture under reduced pressure is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from ethyl acetate / hexane gives 1-acetoxymethyl 1-8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine as a colorless product

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with a melting point of 151-152 °. For analytical purposes this will be Product recrystallized from ethyl acetate / ether.

Example 68

0.3 g of sodium methoxide becomes a solution of 1 g of l-acetoxymethyl-S-chloro-S- (2-fluorophenyl) -4H-imidazo [1,5-a] - [1,4] benzodiazepine given in 20 ml of methanol. The reaction mixture is allowed to stand for 10 minutes at room temperature, whereupon the deposited crystals are collected and washed with aqueous methanol, methanol and ether. Colorless is obtained 8-chloro-6- (2-fluorophenyl) -1-hydroxymethyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine. An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 258-260 °. .

Example 69

A mixture of 0.2 g of 8-chloro-6- (2-fluorophenyl) -1-hydroxymethyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine, 20 ml of methylene chloride and 1 g of activated manganese dioxide is stirred for 2 hours at room temperature. The manganese dioxide is obtained by filtering removed by Celite and the filtrate is evaporated. By crystallizing the residue from methylene chloride / ethyl acetate / hexane 8-chloro-6- (2-fluorophenyl) -4H-imidazo- [1,5-a] [1,4] benzodiazepine-1-carboxaldehyde is obtained as colorless crystals with a melting point of 182-183 °.

Example 70

13.7 g (0.077 M) N-bromosuccinimide are added to a stirred solution of 10 g (0.030 M) 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [ l, 4] benzodiazepine given in 450 ml of chloroform and 30 ml of glacial acetic acid. The reaction mixture is during Stirred under reflux for 1 1/2 hours and then cooled. The reaction mixture is saturated with sodium bicarbonate solution washed and evaporated. The oily residue is 150 g

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chromatographed on neutral aluminum oxide (Woelm). First the impurities are removed with methylene chloride and then the desired product with ethyl acetate. The one you want Fractions containing the product are combined and evaporated. Crystallization of the residue from ether is obtained

e- (2-fluorophenyl) -l-methyl-4H-imidazo [l, 5-a] -

[1,4] benzodiazepine with a melting point of 201-205 °. An analytical sample is recrystallized from ether / hexane and shows the Melting point 203-205 °.

Example 71

1.25 g (0.006 M) phosphorus pentachloride becomes one Suspension of 1.85 g (0.005 M) 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid given in 250 ml of methylene chloride. After stirring for 30 minutes in an ice bath, first 15 ml of diethylamine and then 100 ml of 10% strength aqueous sodium carbonate solution added. The two-phase system is stirred for 30 minutes at room temperature. the organic phase is separated off, dried over sodium sulfate and evaporated. By crystallization of the residue Methylene chloride / ether gives 8-chloro-N, N-diethyl-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide from melting point 182-188 °. An analytical sample is recrystallized from ethyl acetate / hexane and shows the Melting point 183-185 °.

Example 72

5 ml of 2- (dimethylamine) ethylamine become a solution of the acid chloride of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (prepared as in Example 71 from 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride) in 250 ml of methylene chloride given. After adding 100 ml of aqueous sodium carbonate solution, the reaction mixture is at room temperature for 30 minutes

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touched. The methylene chloride phase is separated off, dried and evaporated. By crystallization of the residue 2-propanol / ether gives 8-chloro-N- (2-dimethylaminoethyl) -6- (2-fluorophenyl) -l-methyl-'iH-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide from melting point 209-211. An analytical sample is recrystallized from ethyl acetate / hexane and shows the Melting point 210-213 °.

Example 73

20 ml of 25% strength methanolic ammonia become a solution of the acid chloride of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid (prepared as in Example 71 from 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride) in 250 ml of methylene chloride. After stirring for 10 minutes, 50 ml of 10% aqueous Sodium carbonate solution is added, whereupon the mixture is stirred for a further hour at room temperature. The methylene chloride phase is separated off, dried and evaporated. The residue is dissolved in a mixture of methylene chloride and ethanol. The solution is filtered through silica gel and the filtrate is evaporated. By crystallizing the residue 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3-carboxamide is obtained from ethanol as colorless crystals. An analytical sample is made from ethanol / tetrahydrofuran recrystallized and has a melting point of 300-305 °.

Example 74

4 ml of dimethylamine become a solution of the acid chloride of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylic acid (prepared as in Example 71 from 1.85 g (0.005 M) 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3- carboxylic acid and 1.25 g (0.006 M) phosphorus pentachloride) in 250 ml of methylene chloride. After stirring for 1 hour at room temperature, the

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Washed reaction mixture with 10% aqueous sodium carbonate solution, dried and evaporated. The residue is on 40 g of silica gel are chromatographed, a 5% solution of ethanol in methylene chloride being used as the eluent. Crystallization of the combined clear fractions from ether / hexane gives 8-chloro-6- (2-fluorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxamide as colorless crystals with a melting point of 177-179 °. A lower melting modification (melting point 158-160 °) is also used observed.

Example 75

A solution of 10 g (0.0358 M) 7-cyano-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepin-2-one in 150 ml dry tetrahydrofuran is under nitrogen with 2 .4 g (0.0537 M)
Treated 54% sodium hydride, whereupon the 'reaction mixture is heated to reflux for 1 hour with stirring.
After cooling to 0 °, 13.7 g (0.0537 M) phosphorodimorpholide chloride are added. After 18 hours the reaction mixture is filtered, concentrated to a small volume and mixed with ether. The precipitate obtained is filtered off and recrystallized from a mixture of dichloromethane and ether. 7-Cyano-5- (2-fluorophenyl) -2-bis- (morpholino) -phosphinyloxy-3H-1,4-benzodiazepine is obtained as white rods from
Melting point 194-197 °.

Example 76

To 100 ml of dry Ν, Ν-dimethylformamide are under
Stir and nitrogen give 1.6 g (0.036 M) 54% sodium hydride and 8.3 g (0.038 M) acetitiido diethyl malonate. To
10 g (0.02 M) 7-cyano-5- (2-fluorophenyl) -2-bis (morpholino) phosphinyloxy-3H-1,4-benzodiazepine are added for 30 minutes. After 64 hours, the reaction mixture is poured onto ice water which contains 4 ml of acetic acid. The reaction mixture is filtered and the solid is dissolved in 100 ml dichloromethane.

609815/13 01

The solution is washed with 50 ml of water / over anhydrous Dried sodium sulfate and concentrated to a small volume. It is chromatographed on a Florisil column and eluted with 2 1 dichloromethane, which are discarded. Then with 1 liter of a mixture of dichloromethane and ether (10: 1) and then eluted with 2 liters of ether. The ether fractions are evaporated, and the residue twice from a mixture of Dichloromethane and ether recrystallized, whereby one (acetylamino) [7-cyano-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl] malonic acid diethyl ether obtained as white prisms with a melting point of 138-140 °.

The column is eluted with 1.5 l of a mixture of ethyl acetate and methanol (10: 1). The eluate is concentrated, and the residue crystallized from ether. Obtained by recrystallization from a mixture of dichloromethane and ether 8-Cyano ~ 6- (2-fluorophenyl) -l-methyl ~ 4H-imidazo [l, 5-a] [1,4] -benzodiazepine-3-carboxylic acid ethyl ester as white prisms with a melting point of 272-274 °.

Example 77

A solution of 0.5 g (0.00129 M) 8-cyano-6- (2-fluorophenyl) -l-methyl-4H-imidazoll, 5-a] [l, 4] benzodiazepine-3-carboxylic acid ethyester in 100 ml of ethanol and 10 ml of water is treated with 0.14 g (0.0026 M) potassium hydroxide. After 30 minutes The reaction mixture is evaporated to reflux, and 10 ml of water are added. It is then acidified with acetic acid, filtered and extracted with 20 ml of dichloromethane. The extracts are separated off, dried and evaporated. About 0.2 g Hydrolyzed products are obtained by the filtration and about the same amount from the extracts. This material is added to 3 ml of dry hexamethylphosphoramide, followed by it is heated to 200-205 ° for 30 minutes under nitrogen. After cooling, 50 ml of ice water and 1 ml of ammonium hydroxide are added admitted. The solution is filtered and the filtrate is extracted with 25 ml of dichloromethane. The dichloromethane extracts are

609815/1301

evaporated and dried. The residue is dissolved in water, and the solution is filtered. The combined precipitates are dissolved in dichloromethane and applied to 2 thick layer silica gel plates with a solution of ethyl acetate containing 15% Methanol / developed. The product of Rf value 4-5 is scraped off, stirred with methanol and filtered. By crystallization 8-cyano-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained from a mixture of isopropanol and ether as whitish prisms with a melting point of 198-203.

Example 78

To a solution of 1.6 g (5 mmol) of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 1.2 g (6 mmol) of p-toluenesulfonyl chloride are added to 10 ml of pyridine given. The reaction mixture is left to stand for 19 hours at room temperature, diluted with water and then with. Extracted methylene chloride. The organic extract is dried and evaporated to dryness in vacuo. The residue is crystallized from a mixture of methylene chloride / ether and provides 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-1-methyl-5- (4-methylphenylsulfonyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point of 252-253 °. After recrystallization from tetrahydrofuran, pure product is obtained in the form of yellow Prisms of the same melting point.

To a stirred solution of 2.4 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-1-methy1-5- (4-methylphenylsulfonyl) -4H-imidazo [1.5 -a] [1,4] benzodiazepine in 120 ml of dry tetrahydrofuran, 1.1 g of potassium tert-butoxide are added. After stirring for 2 hours at room temperature, the reaction mixture is poured onto ice water and extracted with a mixture of ether / petroleum ether (1: 1). The organic extract is dried and concentrated to dryness in vacuo. The residue is crystallized from a mixture of ether and petroleum ether and gives 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo- [1,5-a] [1,4] benzodiazepine with a melting point of 152- 153 . Of the

809815/1301

Mixed melting point with an authentic sample does not give depression.

Example 79

To a stirred solution of 1.6 g of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 0.4 g of sodium nitrite are slowly added in 10 ml of acetic acid. After stirring for 1 1/2 hours, the reaction mixture becomes Poured onto ice water, made alkaline with 50% potassium hydroxide solution and extracted with methylene chloride. Of the organic extract is separated off, dried and evaporated to dryness in vacuo. The residue becomes from a mixture crystallizes from methylene chloride and ether and gives 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5-nitroso-1-methyl-4K-imidazo [1,5-a] [1,4] benzodiazepine from melting point 238-240 °. After recrystallization from the same solvent, one obtains pure product in the form of colorless crystals with the same melting point.

To a stirred solution of 1.7 g (4.7 mmol) of 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5-nitroso-1-methyl-4H-imidazo [1,5-a ] · [L, 4] benzodiazepine in 25 ml of dry dimethylformamide, 0.6 g (5 mmol) of potassium t-butoxide are added. After 5 minutes, the reaction mixture is poured onto ice and extracted with methylene chloride. The organic phase is separated off, dried and concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and filtered through 12 g of aluminum (Woelm I) and the filter bed is washed with the same solvent. The filtrate (approx. 120 ml) is dried in vacuo and evaporated. The residue is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -l-methyl ^ H-imidazo- [1,5-a] [1,4] benzodiazepine with a melting point of 139-145. After recrystallization from ether, the product has a melting point of 153-155 ° and shows π
Melting point depression,

from 153-155 ° and shows none with an authentic sample

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Example 80

To a stirred solution of 1.2 g (3.5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-5-oxide in 120 ml of ethanol are slowly 1.2 g (31 mmol) of sodium borohydride admitted. After stirring for 4 1/2 hours at room temperature, the reaction mixture is diluted with 175 ml of water, and the deposited crystals are collected and show a melting point of 246-248 °. After recrystallization from a mixture of methylene chloride / ether gives pure 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5-hydroxy-1-methy1-4H-imidazo [l, 5-a] [1,4] benzodiazepine in the form of colorless needles with a melting point of 251-252.

A solution of 0.3 g of 8-chloro-6- (2-fluorophenyl) -5,6-dihydro-5-hydroxy-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in a mixture of 10 ml of pyridine and 2 ml of acetic anhydride is left to stand for 19 hours at room temperature. The reaction mixture is evaporated to dryness in vacuo. The residue is dissolved in 20 ml of methanol, and 0.2 g of sodium methoxide is added. After standing for 45 minutes At room temperature, the reaction mixture is evaporated to dryness in vacuo. The residue is between methylene chloride and Water distributed. The organic phase is separated off, dried and evaporated to dryness in vacuo. The residue is crystallized from methylene chloride / ether and provides starting material with a melting point of 255-256 °. By narrowing the The filtrate and crystallization of the residue from ether give 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] - [1,4] benzodiazepine from melting point 158-160. The mixed melting point with an authentic sample does not give depression.

6 09816/1301

Example 81

To a solution of 1.6 g (5 mmol) of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine
2.4 ml of 37% formaldehyde are added in 5 ml of formic acid. The reaction mixture is for 5 hours on the
Steam bath heated, then poured onto ice water with 50% iger
Made potassium hydroxide solution alkaline and then extracted with methylene chloride. The organic extract is separated off, dried and evaporated to dryness in vacuo. The residue is crystallized from ether and gives 8-chloro-6- {2-fluorophenyl) -5,6-dihydro-1,5-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point 156-158. After recrystallization from ether, pure product is obtained as colorless prisms from
Melting point 158-159 °.

Example 82

To a stirred solution of 0.98 g (3 mmol) of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazoti, 5-a] [1,4] benzodiazepine in 25 ml of dry dimethylformamide are 0.2 g
(4.3 mmol) 57% sodium hydride added. After 15 minutes
0.4 ml (4.3 mmol) of allyl bromide are added, followed by stirring for a further 6 hours. The reaction mixture is
Poured onto ice water and extracted with a mixture of ether / petroleum ether. The organic phase is separated off, dried and evaporated to dryness in vacuo. The residue is crystallized from a mixture of ether / petroleum ether
and provides S-allyl-e-chloro-δ- (2-fluorophenyl) -5,6-dihydro-imethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine of melting point
140-145 °. After recrystallization from ether, pure ones are obtained
Product in the form of colorless prisms with a melting point of 153-154 °.

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Example 83

A solution of 1.5 g of 8-chloro-5,6-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine in a mixture of 10 ml of pyridine and 5 ml of acetic anhydride are left to stand for 18 hours at room temperature. The reaction mixture is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and washed with dilute potassium hydroxide solution. The organic phase is separated off, dried and evaporated to dryness in vacuo. The residue is crystallized from a mixture of methylene chloride / ether / petroleum ether and gives 5-acetyl-8-chloro-6- (2-fluorophenyl) -5,6-dihydro-1-methyl-4H-imidazo [1 , 5-a ] [1,4] benzodiazepine with a melting point of 185-186 °. After recrystallization from methylene chloride, pure product is obtained in the form of colorless prisms with a melting point of 186-187 °.

Example 84

To a stirred solution of 27.8 g (92 mmol) DL-2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine 27.8 g of zinc dust are slowly added in a mixture of 450 ml of methylene chloride and 300 ml of acetic acid. To After stirring for 4 hours at room temperature, the reaction mixture is filtered through Celite. The filtrate is diluted with ice water, made alkaline with 50% potassium hydroxide solution and with Extracted methylene chloride. The organic extract is separated off, dried and evaporated to dryness in vacuo. Of the The residue is crystallized from ether and gives 2-aminomethyl-7-chloro-2,3,4,5-tetrahydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine from melting point 119-120 °. After recrystallization from ether, pure product is obtained in the form of pale yellow Prisms with a melting point of 127-128 °.

Treatment of a solution of this base in isopropanol with an excess of concentrated hydrochloric acid gives the hydrochloride. By recrystallization

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this salt from a mixture of water and isopropanol gives pure product in the form of pale yellow needles from melting point 268-271 °.

a) A solution of 3 g (10 mmol) of racemic 2-aminomethyl ~ 7-chloro-2,3,4, S-tetrahydro-1-methyl-SH-imidazo [1,5-a] [1,4] - benzodiazepine in a mixture of 30 ml of xylene and 10 ml of triethyl orthoacetate (97%) is heated to reflux for 4 hours. The reaction mixture is diluted with ether and extracted with dilute ice-cold hydrochloric acid. The acid extracts are made alkaline with dilute potassium hydroxide solution and extracted with methylene chloride. The organic phase is separated off, dried and evaporated to dryness in vacuo. The residue is crystallized from ether and gives 8 ~ chloro-6- (2-fluorophenyl) -3a, 4 _/ 5,6-tetrahydro-1-methyl-3H-imidazo [I ₁ .5-a] ■ [1, 4] benzodiazepine (isomer A) with a melting point of 187-189 °. Recrystallization from a mixture of methylene chloride and ether gives pure product in the form of pale yellow prisms with a melting point of 189-190 °.

b) To a stirred solution of 2.5 g of 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -1-methy1-3H-imidazo [1,5-a] [1,4] benzodiazepine 2.5 g of zinc dust are slowly added to a mixture of 100 ml of methylene chloride and 25 ml of acetic acid. After 4 hours Stirring at room temperature, the reaction mixture is filtered through Celite and the filtrate is diluted with ice water with 50% potassium hydroxide solution made alkaline and extracted with methylene chloride. The organic extract is separated, dried and concentrated to dryness in vacuo. The residue is crystallized from ether and gives 8-chloro-6- (2-fluorophenyl) -3a, 4,5,6-tetrahydro-1-methyl-SH-imidazo- [1,5-a] [1,4 ] benzodiazepine (Isomer A), which is identical to the product obtained above. Melting point and mixed melting point 189-190 °. '

809815/1301

c) A solution of 3.2 g (10 mmol) of 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-3H-imidazo [1,5-a] [1,4] benzodiazepine in 50 ml of acetic acid and 10 ml of water in the presence of 0.4 g of prehydrated platinum oxide at room temperature and atmospheric pressure hydrogenated. After 15 minutes, 10 mmol of hydrogen have been taken up. The catalyst is removed by filtration, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and with a Excess of ice-cold dilute sodium carbonate solution washed. The organic phase is separated off, dried and evaporated to dryness in vacuo. The residue will be off a mixture of ether / petroleum ether crystallizes and gives 8-chloro-6- (2-fluorophenyl) -3a, 4,5,6-tetrahydro-1 ~ methyl ~ 3H ~ imidazo [1,5-a] [1,4] benzodiazepine (isomer B) of melting point 108-110. After recrystallization from ether, pure product is obtained in the form of colorless prisms with a melting point 110-112 °.

A mixture of 2.9 g of 8-chloro-6- (2-fluorophenyl) -3a, 4,5,6-tetrahydro-1-methy1-3H-imidazo [1,5-a] [1,4] benzodiazepine, 90 ml of toluene and 15 g of activated manganese dioxide are heated to reflux for 2 hours with stirring. The reaction mixture is filtered through Hyflo and the filtrate is evaporated to dryness in vacuo. The residue is made from ether crystallizes and gives 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine, which does not give a depression of the melting point with an authentic sample.

Example 85

A solution of 3.75 g (0.01 M) 7-chloro-5- (2-fluorophenyl) -a-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml of methanol is in the presence hydrogenated by 1 teaspoon of Raney nickel for 1 1/2 hours under atmospheric pressure. The catalyst is filtered off removed by Celite, and the filtrate is evaporated under reduced pressure, azeotropic with toluene at the end

609815/1301

is evaporated. The residue is dissolved in 20 ml of pyridine and treated with 4 ml of benzoyl chloride. After standing for 15 minutes at room temperature the reaction mixture is partitioned between methylene chloride and IN sodium hydroxide solution. the organic phase is dried and evaporated, with azeotropic evaporation with toluene at the end. By crystallization the residue from ether gives 2- [benzoylamino) methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine with a melting point of 210-213 °. An analytical sample is recrystallized from ethyl acetate / hexane and shows the melting point 217-219 ° (sintering from 150-160 °).

A solution of 1.15 g (2.5 mmol) of 2 - [(benzoylamino) methoxycarbonylmethylene] -7-ChIOr-O- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in 10 ml of hexamethyl phosphoric acid triamide is heated to reflux for 10 minutes. The dark reaction mixture is between water and ether / methylene chloride distributed. The organic phase is washed with water, dried and evaporated. The residue is in Dissolved methylene chloride and filtered through activated aluminum oxide with ethyl acetate. The filtrate is evaporated and the The residue is chromatographed on 20 g of silica gel, one 10% solution of ethyl acetate in methylene chloride is used as a flow agent. By crystallizing the combined clear fractions from ether / hexane give 8-chloro-6- (2-fluorophenyl) -1-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester with a melting point of 208-209 °.

Example 86

To a refluxed solution of 2.66 g (5.77 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine -3-carboxylic acid methyl ester a solution of 755 mg (11.5 mmol) of potassium hydroxide in 10 ml of water is added to 50 ml of methanol. The reaction mixture is heated to reflux for 2 1/2 hours and then evaporated in vacuo. The residue is dissolved in 50 ml of hot vinegar

609815/1301

acid and the solution is then poured onto 100 ml of cold water. The precipitated product is collected with water washed, air-dried and yields 8-chloro-6- (2-fluorophenyl) -l-phenyl-4H-imidazoti, 5-a] [1,4] benzodiazepine-3-carboxylic acid as a whitish solid. An analytical sample is recrystallized from benzene and has a melting point of 267-269 °.

Example 87

A suspension of 1.5 g (3.48 mmol) of 8-chloro-6- (2-fluorophenyl) -l-phenyl-4H-imidazo [1,5-a] ti, 4] benzodiazepine-3-carboxylic acid in 20 ml of mineral oil is heated to 190 ° for 1 1/2 hours with vigorous stirring. The dark suspension is stirred with hexane and extracted twice with IN hydrochloric acid. The aqueous acidic phase is washed once with hexane and then neutralized with 5% aqueous sodium carbonate solution. The precipitated product is collected and air dried. By concentrating the filtrate, additional 8-chloro-6- (2-fluorophenyl) -l-phenyl-4H-imidazotl, 5-a] ti, 4] -benzodiazepine is obtained as a whitish solid. An analytical sample is taken by column chromatography on silica gel Use of ethyl acetate obtained as a flow agent. Melting point 241-243 °.

Example 88

A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -l-phenyl-4H-imidazo ti, 5-a] ti, 4] benzodiazepine-3-carboxylic acid in 0.5 ml of thionyl chloride is heated to reflux for 1/2 hour and then carefully added dropwise Add 70 ml of a cold 40% solution of dimethylamine in water. The precipitated brown solid is collected with Washed water, dried and chromatographed on silica gel, - where ethyl acetate is used as the eluent. One receives Ν, Ν-dimethyl-t8-chloro-6- (2-fluorophenyl) -l-phenyl ^ H-imidazo- [1,5-a] [1,4] benzodiazepine] -3-carboxamide as brown foam.

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■ '' · 254052 ^

Obtained by three recrystallization from acetone / water an analytical sample with a melting point of 221-223.

Example 89

A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -l-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 5 ml of thionyl chloride is refluxed for 1/2 hour and then carefully dropwise added to 70 ml of cold ammonium hydroxide. The pink solid is collected, washed with water, in air dried and chromatographed on silica gel, ethyl acetate being used as the eluent. 8-Chloro-6- (2-fluorophenyl) -1-pheny1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained as brown foam. Trituration with acetone gives an analytical sample in the form of a white Powder melting point 260-262.

Example 90

5.3 g (0.01 M) 7-chloro-5- (2-chlorophenyl) -2- [bis (morpholino) ■ phosphinoyloxy] -311-1,4-benzodiazepine become a mixture of 10 ml of dimethyl malonate, 20 ml of dimethylformamide and 2.2 g (0.02 M) of potassium t-butoxide, which was previously used for 5 minutes was stirred at room temperature under nitrogen, was added. The reaction mixture is then stirred and held for 15 minutes warmed up on the steam bath. After adding 1.5 ml of glacial acetic acid, the product is crystallized by gradually adding water diluted. The precipitated crystals are collected, washed with water, dried in vacuo and give 7-chloro-5- (2-chlorophenyl) ~ 2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine, which is recrystallized from ethyl acetate for analysis purposes and has a melting point of 205-207 °.

60 9 815/1301

A mixture of 12/6 g (0.03 M) 7-chloro-5- (2-chloropheny 1) -2-dimethoxymalonylidene-1,3-dihydro-2H ~ 1,4-benzodiazepine, 300 ml methanol and 2 _r 1 g (0.0375 M) potassium hydroxide is heated to reflux under nitrogen for 4 1/2 hours. 200 ml of methanol are distilled off and the residue is diluted with water. The deposited crystals are collected, washed with water and dried and give 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2 - [(methoxycarbonyl) -methylene] -IH-1,4-benzodiazepine with a melting point of .154-158 °. For analysis purposes, the product is recrystallized from methylene chloride / methanol and has a melting point of 158-159 °.

2.2 g (0.031 M) sodium nitrite are added in portions over 5 minutes to a stirred solution of 7.2 g (0.02 M) 7-Chloro-5- (2-chlorophenyl) -2,3 ~ dihydro-2 - [(methoxycarbonyl) methylene] -IH-1,4-benzodiazepine placed in 75 ml of glacial acetic acid. After stirring for a further 15 minutes, the reaction mixture becomes diluted with 100 ml of water, whereupon the precipitated Crystals are collected and washed with water, methanol and ether. Crude 7-chloro-5- (2-chlorophenyl) -a ~ hydroxyimino ~ 3H-1,4-benzodiazepine-2-acetic acid methyl ester is obtained, which is recrystallized from tetrahydrofuran / methanol and yields yellow crystals with a melting point of 223-225 ° (decomp.).

A solution of 3.9 g (0.01 M) 7-chloro-5- (2-chlorophenyl) -a-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 100 ml of tetrahydrofuran and 50 ml of methanol is in the presence of 2 teaspoons of Raney nickel for 1 1/2 hours Hydrogenated at atmospheric pressure. The catalyst is removed by filtration. The filtrate is evaporated, with the Final azeotropic evaporation with toluene. The residue is dissolved in 20 ml of ethanol. After adding 3 ml of triethyl orthoacetate and 0.2 ml of ethanolic hydrochloric acid (10%), the reaction mixture is heated to reflux for 15 minutes and then evaporated to dryness. The residue is between methylene chloride and saturated aqueous bicarbonate solution

6098 15/130 1

distributed. The organic phase is separated off over sodium sulfate dried and evaporated. Crystallization of the residue from methylene chloride / ether gives 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester from melting point 225-227. An analytical sample is recrystallized from 2-propanol and ethyl acetate and shows the melting point 228-230 °.

Example 91

A solution of 1.2 g (3 mmol) of 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester in 10 ml of tetrahydrofuran is converted to a suspension, cooled to 10 °, of 0.4 g (10 mmol) of lithium aluminum hydride given in 30 ml of ether. After the addition has ended, the reaction mixture is at room temperature for 10 minutes stirred and hydrolyzed by adding 2 ml of water. The inorganic material is filtered off and the filtrate is evaporated. Crystallization of the residue from methylene chloride / ether gives 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl ~ l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine with a melting point of 215-217 °. An analytical sample is made Tetrahydrofuran / hexane recrystallizes and has a melting point of 217-218 °.

Example 92

7.8 g (0.02 M) of 7-chloro-5- (2-chlorophenyl) -a-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester are heated in a mixture of 200 ml of tetrahydrofuran and 100 ml of ethanol dissolved. The solution is hydrogenated in the presence of 2 teaspoons of Raney nickel for 2 hours at atmospheric pressure. The catalyst is removed by filtering through Celite and the filtrate is evaporated under reduced pressure. Crystallization of the residue from ethanol gives 2- [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepine as orange

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Crystals with a melting point of 115-117 ° (decomp.) · By recrystallization this solvated product from ether / hexane is obtained, yellow needles with a melting point of 145-150 (Decomposition).

0.25 ml of acetaldehyde becomes a solution of 0.5 g 2 - [(Amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepine given in 25 ml of methylene chloride. After the addition of molecular sieve 5A, the reaction mixture is stirred for 15 minutes at room temperature. On that 1 g of activated manganese dioxide is added and for a further 30 minutes touched. The solid is separated by filtering through Celite and the filtrate is evaporated. Crystallization of the residue from ethyl acetate / hexane is obtained Methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylate with a melting point of 228-230 °.

Example 93

A stirred suspension of 4 g (0.09 M) of a 54% Dispersion of sodium hydride in mineral oil in 315 ml of dimethylformamide is made under nitrogen in several portions 21 g (0.096 M) diethylacetamidomalonate treated. After stirring for a further 30 minutes at room temperature, all at once 31.4 g (0.06 M) 7-chloro-5- (2-chlorophenyl) -2- [bis (morpholino) -phosphinyloxy] -3H-1,4-benzodiazepine admitted. After stirring for a further 7 hours at room temperature, the mixture becomes black Poured onto ice and acetic acid with stirring and diluted with 2 l of water, a cream-colored solid being obtained. The solid is filtered off, washed with water, air-dried and yields acetylamino- [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester. The dried product is stirred with a small amount of 2-propanol while warming on the steam bath until it dissolves entry. A whitish solid is obtained by cooling to room temperature. By recrystallizing a sample

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whitish ones are obtained from an 8-fold amount of ethanol Microneedles with melting point 153-155.

A solution of sodium ethylate is prepared by dissolving 0.8 g (0.04 g atom) of sodium metal in 50 ml of abs. Ethanol, where the solution is protected by a drying tube. To the touched one 10.1 g (0.02 M) of acetylamino- [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester are dissolved in one portion given, followed by a further 5 hours in a dry atmosphere at room temperature stirs. The reaction mixture is acidified with acetic acid and concentrated in vacuo. The residue is diluted between Ammonium hydroxide and methylene chloride distributed. After the phases have separated, the organic phase is dried over sodium sulfate and evaporated under reduced pressure to a brown amorphous solid. The solid becomes anhydrous in 75 ml Dissolved ether and added to a warm solution of 4 g of maleic acid in 200 ml of ether. After decanting a small Part of the brown gum, the solution is concentrated on the steam bath to a volume of approximately 100 ml. By Cooling to room temperature and occasional scraping results in crystallization after about 30 minutes. As soon as the Crystallization is complete, the orange crystals are filtered off, washed with ether, air-dried and provide 2 - [(acetylamino) ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-1,4-benzodiazepine maleate. By recrystallizing a small sample from ethyl acetate

(5 ml / g) yellow microneedles with a melting point of 139-142 ° (decomp.) Are obtained.

A solution of 3.2 g (0.0073 M) 2 - [(acetylamino) ethoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in 15 ml of hexamethylphosphoramide is heated to 200-210 ° for 10 minutes under nitrogen and with stirring. After cooling to room temperature, the solution is poured onto ice water and diluted with water until the precipitation is complete is. The brown solid is filtered off, washed with water

6098 15/1301

wash and air dry. The solid is dissolved in ethyl acetate (2 ml / g) with stirring, crystallization immediately occurring again he follows. The brown solid is filtered off, washed with ethyl acetate / petroleum ether (1: 1) and air-dried and gives 8-chloro-6- (2-chlorophenyl) -l-methyl- ^ H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester. By recrystallizing a sample from methylene chloride / ethyl acetate with removal of the methylene chloride by boiling gives whitish Needles melting point 214-215.

Example 94

A stirred solution of 4.1 g (0.01 M) 8 ~ chloro-6- (2-chlorophenyl) -1-methyl 1-4H-imidazo [1,5-a] [1,4] benzodiazepine carboxylic acid ethyl ester in 100 ml of methanol containing 3 ml of water and 1.2 g (0.02 M) of potassium hydroxide, during 4 1/2 Heated to reflux under nitrogen for hours. The methanol is then removed under reduced pressure. The residue is dissolved in cold water and acidified with acetic acid. A whitish solid is obtained, which on overnight the air is dried and 8-chloro-6- (2 ~ chlorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid supplies. By recrystallization of a sample from methylene chloride / ethanol (1: 1) white platelets with a melting point of 265-267 ° (decomp.) Are obtained.

Example 95

A stirred suspension of 1.2 g (0.0031 M) 8-chloro-6- (2-chlorophenyl) Ethyl -1-methy 1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate in 25 ml of methylene chloride is cooled in an ice bath and added in portions with 0.7 g (0.004 M) Treated with phosphorus pentachloride. The reaction mixture is protected by a drying tube and for an additional 30 minutes stirred in the cold, in which time most of the solid will dissolve. With continued cooling and stirring is the reaction mixture for 5 minutes with gaseous

60981 B / 1301

Treated ammonia and for another 30 minutes in the Cold stirred. The reaction mixture is evaporated to a pale solid in vacuo. This is diluted with stirred aqueous ammonia, filtered, washed with water and air dried. 8-Chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide is obtained. Recrystallization of a sample from methylene chloride / ethanol (2: 1) yields white plates with a melting point 318-320 ° (decomp.).

Example 96

3 ₇ 7 g (0.01 M) 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyll-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine are added to 20 ml with stirring Thionyl chloride given. After stirring for 30 minutes at room temperature, the hydrochloride of the product is crystallized out by dilution with 30 ml of ethyl acetate and 100 ml of ether. The crystals are collected, washed with ether ■ and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride phase is dried and evaporated. The residue is crystallized from ether and gives 8-chloro-3-chloromethyl-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] ti, 4] benzodiazepine as colorless crystals, which at slow Heating up does not melt, but only when inserting the capillary at 200-210. An analytical sample is recrystallized from ethyl acetate / hexane.

Example 97

A mixture of 2 g e-chloro-S-chloromethy1-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine, 10 ml Dimethylamine and 10 ml of tetrahydrofuran are heated to 100 ° in a closed tube for 2 hours. The solvents are evaporated and the residue is partitioned between methylene chloride and 10% aqueous sodium carbonate solution. The organic phase is dried and evaporated. Of the The residue is crystallized from ether and yields 8-chloro

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6- (2-chlorophenyl) -S-dimethylaminomethyl-1-methyl- ^ H -imidazo- [1,5-a] [1,41LeHZOdIaZePIn with a melting point of 136-138 °.

This product is dissolved in 10 ml of ethanol and treated with 2 equivalents of ethanolic hydrochloric acid. By diluting with ether one obtains 8-chloro-6- (2-chlorophenyl) -3-dimethylaminomethyl-1-methyl-4H-imidazo [1,5 ~ a] [1,4] benzodiazepine-dihydrochloride-ethanol in the form of colorless crystals, which are recrystallized from ethanol / ether for analysis purposes and have a melting point of 275-277 °.

Example 98

A mixture of 1 g of 8-chloro-3-chloromethyl 1-6- (2-chlorophenyl) -l-methyl-4H-imidazo [l, 5-a] [1,4] benzodiazepine 250 mg Potassium cyanide and 20 ml of dimethylformamide are heated on the steam bath for 3 hours while stirring. After diluting the reaction mixture is extracted with methylene chloride using water. The extracts are washed with water and dried and evaporated. The residue is chromatographed on 30 g of silica gel, methylene chloride / ethyl acetate (1: 2) is used as an eluant. Crystallization of the clear fractions from ether gives 8-chloro-6- (2-chlorophenyl) -3-cyanomethyl-1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine from melting point 212-214. An analytical sample ■ is recrystallized from ethyl acetate / hexane and shows the melting point 215-217 °.

Example 99

A suspension of 17 g (0.05 M) 7-chloro-l _/ 3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine-4-oxide in 200 ml of tetrahydrofuran and 100 ml of methanol is hydrogenated in the presence of 17 g of Raney nickel at an initial pressure of 155 psi for 24 hours. The catalyst is removed by filtration and the filtrate is evaporated. Of the

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The residue is dissolved in 50 ml of 2-propanol and put on the steam bath warmed up. The salt obtained after adding 17 g of warm maleic acid in 60 ml of ethanol is obtained by cooling in an ice bath crystallized. 2-Aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine dimaleate is obtained in the form of yellow crystals with a melting point of 196-198 °.

8.0 g (0.015 M) 2-aminomethyl-7 ~ chloro-2,3 ~ dihydro ~ 5 ~ (2-fluorophenyl) -IH-1,4-benzodiazepine dimaleate is between Methylene chloride and aqueous ammonia distributed. The methylene chloride solution is washed with water over sodium sulfate dried and evaporated. The residue is dissolved in 50 ml of pyridine. After adding 10 ml of acetic anhydride, the The mixture was heated on the steam bath for 4 hours. The reaction mixture is evaporated under reduced pressure the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from methylene chloride / ether with seeding gives l-acetyl-2-acetylaminomethyl-7-chloro-2,3-dihydro ~ 5- (2-fluorophenyl) -IH-1,4-benzodiazepine of melting point 213-215. The seed crystals are obtained by chromatography on silica gel (40-fold amount), a 10% solution of Ethanol in methylene chloride is used as the eluent. An analytical sample is recrystallized from ethyl acetate / hexane and shows the melting point 215-217 °.

A mixture of 0.5 g of l-acetyl ^ -acetylaminomethyl -? - chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-I, 4-benzodiazepine and 10 g of polyphosphoric acid is heated to 150-170 ° for 10 minutes. The cold reaction mixture is dissolved in ice water, and the solution was made alkaline with ammonia. The precipitated base is extracted with methylene chloride. the Extracts are washed with water, dried over sodium sulfate and evaporated. The residue is on 10 g of silica gel chromatographed using a 20% solution of methanol in methylene chloride as the eluent. The clear ones

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25A0522

Fractions are combined and evaporated. The residue is crystallized from ether and gives 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-3H-imidazo [1,5-a] [1,4] -benzodiazepine from melting point 142-144.

Example 100

A solution of 2.9 g (0.00927 M) 2,3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-1 H-1,4-benzodiazepine-4-oxide in a mixture of 1 teaspoon of Raney nickel, 90 ml of tetrahydrofuran and 45 ml of methanol is hydrogenated for 2.3 hours at atmospheric pressure and room temperature. The reaction mixture is filtered and the catalyst is washed with dichloromethane. The combined filtrates are evaporated and the oil obtained is dissolved in 50 ml of dichloromethane. The dichloromethane solution is diluted with 50 ml of ammonium hydroxide washed, dried over anhydrous sodium sulfate and evaporated to dryness. To the solution add 2.2 g (0.019 M) maleic acid given in 15 ml of ethanol, and the oil crystallizes out after the addition of ether. 2-aminomethyl-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine dimaleate hemihydrate is obtained. Recrystallization from a mixture of methanol and ether gives the product as yellow rods Melting point 147-150 °.

A solution of 4.0 g (0.0149 M) of the base of 2-aminomethyl-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine dimaleate hemihydrate in 125 ml of absolute ethanol is mixed with 4 g (0.0247 M) Trxathylorthoacetat and 0.5 g (0.00263 M) Treated p-toluenesulfonic acid. The reaction mixture is heated to reflux for 2 hours and then evaporated to dryness. The oil obtained as a residue is dissolved in 50 ml Dissolved dichloromethane. The solution is washed with 50 ml of dilute ammonium hydroxide over anhydrous sodium sulfate dried, evaporated to give crude 3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-SH-imidazo [1,5-a] [1,4] benzodiazepine in the form of an oil.

6 0 9 8 15/1301

a) This crude product is dissolved in 100 ml of toluene and mixed with 18 g activated manganese dioxide treated. The reaction mixture is heated to reflux for 3.5 hours, with a Water separator is used. The reaction mixture is filtered through Celite, and the precipitate is washed with 100 ml Tetrahydrofuran and then 100 ml dichloromethane. The combined filtrates are evaporated and the residue in 25 ml of dichloromethane dissolved. This solution is chromatographed through a Florisil column, first using dichloromethane and then ether is used as the eluant. Elute with ethyl acetate and then with a 10% solution of methanol in Ethyl acetate gives a crude product which is crystallized from ether and then from ethyl acetate and 6- (2-fluorophenyl) -1-methyl-4H ~ imidazo [1,5-a] [1,4] benzodiazepine as white prisms with a melting point of 164-168.

b) A solution of 1.2 g (0.0041 M) 3a, 4-dihydro-5- (2-fluorophenyl) -l-methyl-3H-imidazo [1,5 ~ a] [1,4] benzodiazepine in 50 ml of mesitylene and 0.5 g of 10% palladium carbon is heated to reflux for 28 hours with stirring. The reaction mixture is filtered and evaporated to dryness. By Crystallization of the residue from ethyl acetate gives 6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine as white prisms with a melting point of 162-167 and a mixed melting point with authentic product from 162-168.

Example 101

A solution of 0.3 g (0.00103 M) 6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in 2 ml of concentrated sulfuric acid is cooled to 0 and 'dropwise with a solution of 0.11 g (0.0011 M) potassium nitrate in 1.5 ml of concentrated sulfuric acid. After 18 hours Allowing to stand at room temperature a further 20 mg (0.0002 M) potassium nitrate are added and the reaction mixture is continued for more Stirred for 5 hours. The reaction mixture is then poured onto ice, made basic with ammonium hydroxide and with 50 ml

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- 136 - ·

Dichloromethane extracted. The extract is over anhydrous Dried sodium sulfate and evaporated to dryness. The oil obtained is dissolved in 3 ml of dichloromethane and poured onto a Silica gel plate applied, which is developed with a mixture of ethyl acetate and ethanol (3: 1). That nitrided Product is scraped off the plate and stirred with a mixture of methanol / dichloromethane (lsi) and filtered. the The filtrates are evaporated and the residue is crystallized from methanol. By recrystallization from a mixture of Dichloromethane and petroleum ether give 6 ~ (2-fluoro-S-nitrophenyl) -l-methyl ~ 4H- imidazo [1,5-a] [1,4] benzodiazepine as white prisms with a melting point of 199-203.

Example 102

41.3 g of e-chloro-l ^ -dimethyl-ö- (2-fluorophenyl) -4H-imidazo ~ [1,5-a] [1,4] benzodiazepine dihydrochloride is between Methylene chloride and aqueous ammonia distributed. The methylene chloride solution is washed with water over sodium sulfate dried and evaporated. The free base is obtained in this way. This is dissolved in 50 ml of 2-propanol, and the Solution is treated with a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution is gradually added to 300 ml Diluted ether. The precipitated crystals are collected, dried and give 8-chloro-1,4-dimethy1-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate, which after recrystallization from ethanol / ether melts at 130-132 °.

Example 103

A solution of 5 g (0.00153 M) 8-chloro-6- (2.-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in 75 ml of dry ethylene dichloride is cooled in an ice bath and treated with 5 g (0.0352 M) of boron trifluoride etherate. After 10 minutes a solution of 4 g (0.091 M) of ethylene oxide in 5 ml of ethylene dichloride is added with stirring. The reaction mixture is Left to stand for 1 hour at room temperature and then with a

609815/1301

Solution of potassium carbonate in water made basic. The organic phase is separated off over anhydrous sodium sulfate dried and evaporated. The residue is dissolved in 50 ml of dichloromethane and filtered through 150 g of Florisil. The Florisil is eluted with 750 ml of dichloromethane and then with 750 ml of ether.

The dichloromethane solution is evaporated and the residue is distributed between 100 ml of ether and 100 ml of 0.5N hydrochloric acid. The acidic phase is separated off with ammonium hydroxide made basic and extracted with 100 ml dichloromethane. The dichloromethane phase is dried and evaporated. That as OeI obtained residue is dissolved in 15 ml of isopropanol and treated with 0.8 g (0.0069 M) maleic acid. The solution is heated on the steam bath for 5 minutes, then cooled and mixed with ether. The precipitate obtained is filtered and recrystallized from a mixture of methanol / ether, 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, IIH-imidazo C1,5-a] oxazolo [3,2 ~ d] [1,4] benzodiazepine maleate is obtained as white prisms with a melting point of 195-200 °. That The ether eluate from the Florisil column is concentrated and filtered and crystallized from ether, the base being obtained as white prisms with a melting point of 178-180 °.

Example 104

A stirred solution of 29.9 g (0.1 M) 1,3-dihydro-5- (2-fluorophenyl) -7-nitro-2H-1,4-benzodiazepin-2-one in 500 ml of dry tetrahydrofuran, 5.5 g (0.125 M) of a 54% strength dispersion of sodium hydride are added in portions under argon treated in mineral oil, followed by stirring for a further hour. For the black solution, ground in one portion 38 g (0.15 M) dimorpholinophosphine chloride are added, whereupon stirring is continued under argon for 8 hours. The received black reaction mixture is filtered and concentrated in vacuo at 50 ° to a black gum. This rubber will stirred at room temperature in 75 ml of ethyl acetate, with crystalline

6098 1 S / 1301

sation occurs and a paste is obtained. After 30 minutes of cooling in an ice bath, the reaction mixture is filtered and the The light brown solid obtained is washed three times with 35 ml portions of ether / ethyl acetate (2: 1) and finally with ether. Air drying gives almost pure 5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -V-nitro-SH-l ^ -benzodiazepine. By recrystallization from a 15-fold amount of ethyl acetate, whitish needles with a melting point of 169-172 are obtained.

A stirred suspension of 0.85 g (0.018 M) of a 54% dispersion of sodium hydride in mineral oil in 55 ml of dry Dimethylformamide is treated in portions with 3.5 g (0.016 M) diethyl acetamidomalonate under argon. After 30 minutes 5.2 g (0.01 M) 5- (2-fluoro-phenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine are stirred in one portion added, whereupon the mixture is stirred under argon for a further 7 hours. The black reaction mixture will Poured onto a stirred mixture of ice and acetic acid, diluted with water to give a tan solid. The solid is washed with water, air-dried and yields a residue. Thin layer chromatography (Ethyl acetate) shows three yellow spots with Rf values 0.8, 0.5 and 0.25. By chromatography of the product from the Rf value 0.25 on silica gel, using ethyl acetate as the eluent, gives 6- (2-fluorophenyl) -1-methy1-8-nitro-4H-imidazo [l, 5-a] [l ^ lbenzodiazepine-S-carboxylic acid ethyl ester as yellow-brown solid. Recrystallization of a sample from ethyl acetate (5 ml / g) by dissolving in hot ethyl acetate and Cooling in an ice bath gives yellow prisms with a melting point of 231-233 °.

Example 105

11 g (0.25 M) of a 45% dispersion of sodium hydride in mineral oil is added in portions under nitrogen to a stirred solution of 63.2 g (0.2 M) 7-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4-benzodiazepin-2-one added to 1 liter of tetrahydrofuran. The reaction mixture is on for 1 hour

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Heated the steam bath, cooled to room temperature and Treated in portions with 56.2 g (0.3 M) dimorpholinophosphine chloride. The reaction mixture is for a further 5 hours stirred at room temperature and then filtered through celite. By concentrating the filtrate in vacuo and boiling the dark A residue in ether gives 7-bromo-2- [bis (morpholino) -phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine as brown crystals. A sample is made by dissolving in 2 ml of methylene chloride, filtering, diluting with 10 ml of ethyl acetate and cooling in an ice bath recrystallizes and gives light brown flakes with a melting point of 180-182 ° (decomp.).

43 g (0.2 M) diethyl acetamidomalonate is made into a suspension of 10 g (0.2 M) of a 50% sodium hydride dispersion given in mineral oil in 500 ml of dry dimethylformamide. The reaction mixture is under argon for 1 hour Room temperature and stirred on the steam bath for 20 minutes. After adding 53.4 g (0.1 M) 7-bromo-2- [bis (morpholino) phosphinyloxy] 5- (2-pyriayl) -3H-1,4-benzodiazepine, the reaction mixture is brought back to room temperature. After stirring for 1 hour at room temperature it is heated again on the steam bath for 2 hours. The cooled solution is between water and methylene chloride / ether distributed. The organic phase is separated off, washed with water, dried and evaporated. The residue is crystallized with seeding from ethyl acetate / ether and gives 8-bromo-1-methy1-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid-ethy ! ester as whitish crystals with a melting point of 240-243 °. The seed crystals are obtained by chromatography on 30 times the amount of silica gel, a 5% solution of methanol in Ethyl acetate is used as the eluent. An analytical sample is crystallized from ethyl acetate and shows the melting point 243-244 °.

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Example 106

A mixture of 2.15 g (5 mmol) of 8-bromo-1-methyl-6- (2-pyridyl) ~ 4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester, 50 ml of methanol, 0.84 g (15 mmol) of potassium hydroxide and 2.5 ml of water are heated to reflux for 5 hours. After evaporating the major part of the methanol, the residue is partitioned between water and ether. The watery Phase is acidified with acetic acid and extracted with methylene chloride. The extracts are dried and evaporated. Crystallization of the residue from methylene chloride / ethyl acetate gives 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid as colorless crystals, which are recrystallized from methanol for analysis purposes and have a melting point of 245-250 ° (decomp.) with the preceding Show sintering.

Example 107

A solution of 1.3 g of 8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 20 ml Aethy.leng3.ykol is heated to reflux for 1 hour. The reaction mixture is between water and methylene chloride / Toluene distributed. The organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from ether / 2-propanol gives 8-bromo-1-methy1-6- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine as brown crystals. An analytical sample is recrystallized from ethyl acetate / hexane and shows the Melting point 189-190 °.

Example 108

A stirred suspension of 7.8 g (0.174 M) of a 54% dispersion of sodium hydride in mineral oil in 480 ml of dimethylformamide is treated in portions with 39 g (0.18'M) 'diethylacetamidomalonate under argon. After about 30 minutes it will be

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48 g (0.096 M) 7-chloro-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine in one serving added, whereupon the mixture is stirred under argon and room temperature for a further 5 hours. A dark reaction mixture is poured onto a mixture of ice and glacial acetic acid while stirring and yields a light brown solid, which is filtered off, washed with water and partially air dried. The moist solid is dissolved in methylene chloride solved. After the aqueous phase has been separated off, the solution is dried over sodium sulfate, filtered and reduced under reduced pressure Pressure evaporated to a brown foam. The foam is dissolved in isopropanol (4 ml / g) while stirring and for 1 hour kept at room temperature with occasional scratching, whitish crystals precipitate. You add one equal amount of petroleum ether (30-60 °) and keeps the reaction mixture for 30 minutes before filtering Room temperature. Washing with petroleum ether and air drying gives diethyl acetylamino [7-chloro-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl] malonic acid from a melting point of 150-180 °. üinkristallisatiön a sample from ethanol (10 ml / g) increases the melting point to 185-195 °, sintering being observed beforehand.

A stirred solution of sodium ethoxide (made from 0.2 g [0.01 g atoms] of sodium metal in 25 ml of absolute Ethanol) is mixed with 2.4 g (0.005 M) of acetylamino [7-chloro-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2-yl] malonic acid diethyl ester treated, followed by stirring using a drying tube for 5 hours at room temperature. The unusual one yellow solid is collected by filtration, washed with ethanol and then with ether and air-dried. Of the Pesticide is distributed between water and methylene chloride, acidified with acetic acid and again with methylene chloride extracted. After washing with dilute ammonium hydroxide solution, the methylene chloride extracts are dried over sodium sulfate and then evaporated in vacuo to a brown foam.

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A solution of 1 g (0.0024 M) of the base in 25 ml of ether is mixed with a solution of 0.56 g (0.0048 M) of maleic acid in 25 ml Mixed ether, whereupon the reaction mixture is kept at room temperature. After a few minutes you get under the occasional Scratch orange crystals. These are collected by filtration, washed with ether and air-dried and provide 2 - [(acetylamino) ethoxycarbonylmethylene] -7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine maleate with a melting point of approx. 150. By recrystallization from 30 ml of ethyl acetate and concentration to half the volume and below Inoculation gives orange prisms with a melting point of 149-151.

6.3 g (0.015 M) crude 2 - [(acetylamino) ethoxycarbonylmethylene] -7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine, which from the maleate by making it basic with ammonia, extracting with methylene chloride and evaporating in Vacuum has been obtained, is dissolved in 35 ml of hexamethylene phosphoramide and heated to 200-210 for 5 minutes with stirring. The dark solution is cooled, poured onto ice water and yields a brown solid. The solid is filtered off, washed with water and partially air dried. The moist solid is dissolved in methylene chloride, the Solution dried over sodium sulfate and evaporated under reduced pressure, whereby 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester as brown foam. By recrystallizing 1 g of this foam from 5 ml of ethyl acetate and 5 ml of petroleum ether (30-60 °) the product is obtained as a light brown prisms which melt at 176-179 and slowly solidify again and melt again at 195-198.

Example 109

43 g (0.2 M) diethylacetamidomalonate becomes a suspension of 10 g (0.2 M) sodium hydride (50% dispersion in mineral oil) in 500 ml of dry dimethylformamide. That

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The reaction mixture is heated to 50 ° for 30 minutes under argon. After adding 53 g (0.1 M) 5- (2-chlorophenyl) -2- [bis (morpholino) phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine the reaction mixture is heated on the steam bath for 1 hour. The cold reaction mixture is between Water and methylene chloride / ether distributed. The organic phase is washed with water, dried and evaporated. Of the The residue is chromatographed on 1 kg of silica gel, using ethyl acetate is used as an eluant. The clear fractions are combined and evaporated. By crystallizing the A residue from methylene chloride / ether gives 6- (2-chlorophenyl) -l-methyl-S-nitro-4H-imidazo [1,5a] [1,4 ·] -benzodiazepine-3-carboxylic acid ethyl ester as light yellow crystals, melting point 233-234. An analytical sample is made from ethyl acetate recrystallized and has a melting point of 234-235 °.

Example 110

A mixture of 4.25 g (0.01 M) 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester, 100 ml of methanol, 1.12 g (0.02 M) of potassium hydroxide and 4 ml of water are added under nitrogen for 3 hours heated to reflux. The residue obtained after evaporation of the main amount of methanol is mixed with water and ether distributed. The aqueous phase is washed with ether, acidified with acetic acid and extracted with methylene chloride. the Extracts are dried and evaporated. Obtained by crystallization of the residue from methylene chloride / ethyl acetate one 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] -benzodiazepine-3-carboxylic acid of melting point 272-274 ° (dec.). An analytical sample is recrystallized from methanol / ethyl acetate and shows a melting point of 274-276 ° (dec.).

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Example 111

A mixture of 1.5 g of 6- (2-chlorophenyl) -l-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 10 ml of ethylene glycol is heated to reflux for 1 hour. The reaction mixture is partitioned between methylene chloride and toluene and saturated sodium bicarbonate solution. The organic phase is washed with water, dried and evaporated. The residue is dissolved in 10 ml of 2-propanol and treated with 0.6 g of maleic acid. The salt crystallizes out by adding ether to the warm solution. It will collected, washed with 2-propanol and ether and gives 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate as brown crystals, which are recrystallized from 2-propanol for analysis purposes and the Show melting point 150-152 °. The base released from this salt crystallizes from ethyl acetate / hexane and shows the melting point 170-173 °.

Example 112

6g (0.125 M) sodium hydride dispersion (50% in mineral oil) becomes a solution of 28.1 g (0.1 M) 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one given in 300 ml of dry tetrahydrofuran. After stirring for 1 hour at room temperature 30.2 g (0.12 M) dimorpholinophosphine chloride are added, whereupon the mixture is stirred for a further 4 hours. That The product is crystallized out by adding water and ether. The precipitate is collected and dissolved in methylene chloride solved. The solution is dried and evaporated. The residue is crystallized from ethyl acetate and gives crude 7-Nitro-2- [bis (morpholino) phosphinyloxy] -5-phenyl-SH-1,4-benzodiazepine with a melting point of 208-209 °.

A portion of this material is added to a mixture, heated to 40 for 30 minutes, of 8.6 g (O, O4 M) diethyl acetaminomalonate, 2 g (0.04 M) sodium hydride suspension (50% in mineral

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oil) and 75 ml of dimethylformamide. Then that will The reaction mixture was heated on the steam bath for 30 minutes and then partitioned between water and ether. The organic Phase is washed with water, dried and evaporated. The residue is chromatographed on 250 g of silica gel, whereby Ethyl acetate is used as the eluent. The combined clear fractions are evaporated and the residue crystallized from methylene chloride / ether. Ethyl 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate is obtained as whitish crystals with a melting point of 240-241 °. An analytical sample is made from ethyl acetate recrystallized.

Example 113

A mixture of 1.95 g (5 mmol) of l-methyl-8-nitro-6-phenyl-4H-iraidazo [l, 5-a] [l _r 4] benzodi-3-zepine-3-carboxylic acid ethyl ester , 50 ml of methanol, 0.56 g (0.01 M) of potassium hydroxide and 2 ml of water are heated to reflux under nitrogen for 3 hours. After partial removal of the solvent, the residue is acidified with 2 ml of glacial acetic acid and partitioned between methylene chloride / containing 10% ethanol / and water. The organic phase is dried and evaporated. Crystallization of the residue from ethyl acetate / methanol gives l-methyl-8-nitro-6-phenyl-4H-imidazo [l, 5-a] [l, 4] benzodiazepine-3-carboxylic acid as straw-colored crystals, which can be used for analysis purposes are recrystallized in the same solvent and have a melting point of 240-243 ° (decomp.).

Example 114

A suspension of 1.2 g of 1-methyl-8-nitro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 15 ml of hexamethylphosphoric triamide is heated to reflux for 3 minutes. The cooled solution is between methylene chloride / ether and aqueous sodium bicarbonate solution. The organic phase is washed with bicarbonate solution,

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dries and evaporated. The residue is chromatographed on 30 g of silica gel, a 3% solution of ethanol in Methylene chloride is used as the eluent. By crystallizing the clear fractions from ether / methylene chloride / Ethyl acetate gives 1-methyl-8-nitro-6-phenyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine from a melting point of 168-170 °. This product is converted into the maleate salt, which after Crystallization from ethyl acetate with 0.5 M solvent shows the melting point 125-128 ° (decomp.).

Example 115

A mixture of 2.45 g (0 _r 07 M) 8-chloro-1- methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, 50 ml pyridine and 7 g of phosphorus pentoxide is refluxed for 15 minutes. The residue obtained after evaporation of the pyridine under reduced pressure is partitioned between ice, 10% sodium carbonate solution and methylene chloride. The organic phase is separated off, dried and evaporated. The residue is chromatographed on 50 g of silica gel, ethyl acetate / methylene chloride (1: 1) being used as the eluent. Crystallization from ethyl acetate / hexane gives 8-chloro-3-cyano-l-methyl-6-pheny 1-4H-imidazo [1,5-a] [1,4] -benzodiazepine with a melting point of 228-229.

Example 116

5 g activated manganese dioxide becomes a solution of 1 g 8-chloro ~ 6- (2-chlorophenyl) -S-hydroxymethyl-l-methyl ^ H-imidazotl, 5-a] [1,4] benzodiazepine in 50 ml of methylene chloride. The reaction mixture is stirred for 2 hours at room temperature. The manganese dioxide is filtered off, and that The filtrate is evaporated. Crystallization of the residue from ethanol gives 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [l, 5-a] [1,4] benzodiazepine-3-carboxaldehyde as colorless crystals with a melting point of 237-239 °. An analytical sample is recrystallized from tetrahydrofuran / ethanol.

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Example 117

A mixture of 1.4 g (4 inMol) of 8-chloro-6- (2-fluorophenyl) 1-methyl-4H-imidazo [1,5 ~ a] [1,4] benzodiazepine-3-carboxaldehyde, 2 ml of triethylamine, 30 ml of ethanol and 0.56 g (8 mmol) of hydroxylamine hydrochloride is added for 1 1/2 hours at room temperature ditched. After dilution with water, crystals precipitate, which are collected and dried. Man receives 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo ti, 5-a] [1,4] benzodiazepine-3-carboxaldoxime from melting point 269-271. An analytical sample is recrystallized from tetrahydrofuran / ethanol and shows the melting point 272-275 °.

Example 118

A solution of 25 g of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo Γ1,5-a] [l, 4] benzodiazepine in 50 ml of water and 50 ml concentrated hydrochloric acid is allowed to stand for 3 hours at room temperature. After adding 250 ml of 2-propanol, the reaction mixture was partly evaporated under reduced pressure without heating. After adding 200 ml of 2-propanol, the partial evaporation repeated. The precipitated crystals are collected and washed well with 2-propanol and ether. 5-aminomethyl-1- [4-chloro-2- (2-fluorobenzoyl) phenyl] _-_ is obtained 2-methylimidazole dihydrochloride with a melting point of 302-307 ° (Zers "). An analytical sample is made from methanol / 2-propanol recrystallized without heating.

Example 119

A mixture of 49.9 g (0.2 mol) of 2-amino-5-chloro-2'-fluorobenzophenone, 38.0 g (0.3 mole) 2,2-dichloropropanal, 18.0 g (0.11 mol) hydroxylamine sulfate and 500 ml of ethanol is during Stirred for 2 days at room temperature.

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The reaction mixture is with vigorous stirring with 200 ml 10% aqueous sodium carbonate solution diluted. A rubber-like one Material precipitates out of solution and the solution is diluted with 1 liter of ice water. The solution is three times 300 ml Dichloromethane extracted. The extracts are combined, dried over sodium sulfate, filtered and in a vacuum to dryness evaporated. The residue is crystallized from dichloromethane and petroleum ether and gives 6-chloro-2- (1,1-dichloroethyl) -1,2-dihydro-4- (2-fluorophenyl) quinazoline-3-oxide as yellow prisms with a melting point of 195-198 ° (decomp.).

3.8 ml of nitromethane are added to 50 ml of dimethylformamide under nitrogen and with stirring. The solution is cooled to 0 and in portions with 1.3 g (0.012 mol) of potassium tert-butoxide offset. The temperature is kept at 0-10 ° using an ice water bath. The reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is cooled to 5 ° and added in portions while stirring 2.2 g (0.006 mol) of the quinazoline were added at 5-9 °. After the addition has ended, the reaction mixture is left to cool for 17 hours stirred at room temperature.

The reaction mixture is poured onto ice water and dichloromethane and neutralized with glacial acetic acid. The dichloromethane solution is washed with water and sodium chloride solution and dried over sodium sulfate. After filtration and evaporation, one obtains an amber residue, which is crystallized from ethyl acetate. The crystals are collected and dried and provide orange 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -S-methyl ^ -nitromethylene ^ H-l ^ -benzodiazepine-oxide as prisms with a melting point of 198-200 °. Pure product is obtained by recrystallization from dichloromethane / ethyl acetate Melting point 216-218 ° (dec.).

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Example 120

A solution of 0.2 g of 3- (benzyloxycarbonylamino) -8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in 10 ml of glacial acetic acid and 2 ml of acetic anhydride is 10%
Palladium-carbon hydrogenated for 1 hour at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated, final azeotropic evaporation with xylene. The residue is chromatographed on 6 g of silica gel, a 10% solution of ethanol in methylene chloride being used as the eluent. Crystallization of the combined clear fractions from ethyl acetate / ether gives 3-acetamino-8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 175-178 °.

Example 121

0.25 g (2.2 mmol) of potassium t-butoxide become one on
-30 ° cooled solution of 0.65 g (2 mmol) 8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in
Given 10 ml of dimethylformamide. After stirring for 10 minutes under nitrogen, 0.2 ml of methyl chloroformate is added in one portion at -30 °. As soon as the reaction mixture has warmed to 0, it is partitioned between methylene chloride and saturated sodium bicarbonate solution. The methylene chloride phase is diluted with benzene, with sodium bicarbonate solution
washed, dried and evaporated. The residue is on
Chromatographed 20 g of silica gel, ethyl acetate being used as the eluent. By crystallizing the combined
clear fractions from ether give 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [l, 5-a] [l, 4] methyl benzodiazepine-4-carboxylate as colorless crystals with a melting point
203-205 °. An analytical sample is recrystallized from ethyl acetate / hexane.

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Example 122

0.14 g (2 mmol) of hydroxylamine become a suspension of 0.37 g (1 mmol) of 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde given in 10 ml of ethanol and 0.5 ml of triethylamine, the reaction mixture is heated on the steam bath until the solution is complete, after which the solution is left to stand for 2 hours. the Precipitated crystals are collected, washed with water, ethanol and ether and give 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldoxime . An analytical sample is recrystallized from tetrahydrofuran / ethanol and has a melting point of 290-292 (decomp.).

Example 12 3

5 ml of an approx. 1 molar solution of methylmagries ium iodide in ether become a solution of 0.37 g (1 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methy1-4H-imidazo [1, 5-a] [1,4] benzodiazepine-3-carboxaldehyde in 10 ml of tetrahydrofuran. After 15 minutes Left to stand at room temperature, the reaction mixture is decomposed with water. The inorganic material will filtered off and washed with methylene chloride. The filtrate is dried and evaporated. By crystallizing the A residue from ether and recrystallization from ethyl acetate / hexane gives 8-chloro-6- (2 ~ chlorophenyl) -3- (1-hydroxyethyl) -l-methyl-4H-imidazo [l, 5-a] [1,4] benzodiazepine as colorless crystals with a melting point of 197-199 °.

Example 124

A solution of 0.1 g of 8-chloro-6- (2-chlorophenyl) -3- (1-hydroxyethyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine in 20 ml of methylene chloride is activated in the presence of 0.5 g Manganese dioxide stirred for 3 hours at room temperature. The manganese dioxide is removed by filtration, and the filtrate is evaporated. The crystalline residue is made from ethyl acetate /

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Hexane recrystallizes and gives B-acetyl-e-chloro-o- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine from melting point 234-236 °.

Example 125

A stirred solution of 12.4 g (0.03 M) 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl ester in 200 ml of methylene chloride is mixed with 12 g (0.07 M) of m-chloroperbenoic acid in portions at room temperature treated. Stirring is then continued for 2 1/2 hours. The solution is washed with IN sodium hydroxide solution, and the cloudy methylene chloride phase is separated off, diluted with methanol and dried over sodium sulfate. By Filtration and evaporation under reduced pressure gives a gum which, by trituration with ether, 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 - Ethyl carboxylic acid 5-oxide as whitish prisms. An analytical sample is made by recrystallizing twice aus.Aethanol / methylene chloride (1: 1) and shows the Melting point 247-249 °.

Example 126

A solution of 0.7 g (0.00203 M) (2-fluorophenyl) - [2- (5-hydroxymethyl-2-methyl-1-imidazolyl) -5-chlorophenyl] methanone in 40 ml of dry dichloromethane is cooled in an ice bath and, with stirring, with 0.22 ml. (0.00227 M) phosphorus tribromide offset. The reaction mixture is stirred for 1 hour at room temperature, then cooled in an ice bath and with 2 ml (0.0328 M) ethanolamine added. The solution is stirred for 2 hours at room temperature, for 1 hour Heated to reflux and then poured onto 50 ml of water. The organic phase is separated off over anhydrous sodium sulfate dried and concentrated to a small volume. The residue is on 4 silica gel plates with a solution of 5% Methanol developed in ethyl acetate. The material with the

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Rf value 0.5 is removed from the plate and treated with methanol. The solution is filtered and the filtrates are evaporated. The residue is crystallized from ether and provides 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, 11H-imidazo [1,5-a] oxazolo ~ "[3, 2 * -d] [1, 4] benzodiazepine. Avg Recrystallization from a mixture of methanol and ether gives pure product in the form of white prisms Melting point and mixed melting point with an authentic sample of 176-181 °.

Example 127

2.4 g (0.02 M) phenylacetaldehyde becomes a solution of 3.8 g (0.01 M) 2 - [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) "1,3-dihydro-2H-1,4-benzodiazepine in methylene chloride given. After adding 10 g of molecular sieve 5A the reaction mixture was stirred for 15 minutes at room temperature and then mixed with 10 g of activated manganese dioxide and stirred for a further 15 minutes at room temperature. The inorganic Material is removed by filtering through celite. The filtrate is evaporated, and the residue is made of ether / Hexane crystallizes and provides l-benzyl-8-chloro-6- (2-chlorophenyl) -4h-imidazo ti, 5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester as colorless crystals with a melting point of 155-158 °. An analytical sample is crystallized from ethyl acetate / hexane and shows the melting point 160-162 °.

Example 128

A mixture of 2 g (4.2 mmol) of 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid methyl ester, 1 g Potassium hydroxide , 50 ml of methanol and 5 ml of water are refluxed for 4 hours under atmospheric pressure and under nitrogen. The residue obtained after evaporation of the solvent is dissolved in water and the solution is acidified with acetic acid. The precipitated crystals are collected, washed with water and dissolved in methylene chloride.

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The solution is dried and evaporated. Crystallization from methylene chloride / ethyl acetate gives l-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo ti, 5-a] [1,4] benzodiazepine-3-carboxylic acid melting point 305-310 (dec.).

Example 129

The product obtained according to Example 128 is suspended in 30 ml of methylene chloride. After adding 0.8 g of phosphorus pentachloride, the reaction mixture is stirred over ice water for 30 minutes. Ammonia gas is then passed in until the basic reaction occurs. After stirring for 15 minutes at room temperature, aqueous ammonia is added and the two-phase mixture is stirred for a further 15 minutes. The methylene chloride phase is separated off _/ dried and evaporated. The crystalline residue is recrystallized from ethyl acetate / methanol, and gives l-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide as a colorless Product with a melting point of 282-284 °.

An analytical sample is chromatographed on a 40-fold amount of silica gel, using methylene chloride / ethyl acetate (1: 1) is used as the eluent. This product has a melting point of 286-288 °.

Example 130

A mixture of 370 mg (1 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methy1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxaldehyde, 10 ml of ethanol and 0.5 ml of 1,1-dimethylhydrazine is heated to reflux for 15 minutes. The residue obtained after evaporation of the solvent is crystallized from ethanol / water and gives 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [l _f 5-a] [l _r 4] benzodia'zepin- 3-carboxaldehyddimethylhyrazone-ethanol (2/1) in the form of light yellow crystals. An analytical sample is recrystallized from ethanol and has a melting point of 238-242 °. The crystals contain

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0.5 equivalents according to the NMR spectrum and analysis Ethanol.

Example 131

1.1 g (5.2 mmol) of phosphorus pentachloride is added to a suspension, cooled in ice water, of 1.6 g (4 mmol) of 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1.5 -a] [1,4] benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride. After stirring in ice water for 30 minutes, a stream of ammonia is passed in until the reaction mixture is basic, whereupon the mixture is stirred for a further hour at room temperature. After adding water, the organic phase is separated off, dried and evaporated. Crystallization of the residue from methanol / ethyl acetate gives 6- (2-chlorophenyl) -l-methyl-8-nitro-4H-imidazoCl ₇ 5-a] - [1,4] benzodiazepine-3-carboxamide as yellowish crystals with a melting point > 300 °. An analytical sample is recrystallized from the same solvent.

Example 132

0.625 g (5.5 mmol) of potassium t-butoxide are added to a solution, cooled to -30 °, of 1.625 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -l'-methyl-4H-imidazo [ 1,5-a] [1,4] benzodiazepine in 20 ml of dimethylformamide. The reaction mixture is stirred at -30 ° for 10 minutes under nitrogen, acidified with 1 ml of glacial acetic acid and then partitioned between aqueous bicarbonate solution and toluene / methylene chloride (3: 1). The organic phase is separated off, dried and evaporated. The residue is chromatographed on 60 g of silica gel, a 25% solution of methylene chloride in ethyl acetate being used as the eluent. The less polar product is first eluted and crystallized from ethyl acetate / hexane and yields 8-chloro-6- (2-fluorophenyl) -l-methy1-6H-imidazo [1,5-a] [I ₇ 4] benzodiazepine with a melting point of 180 -181 °.

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25A0522

Example 133

9.5 ml of nitromethane are under nitrogen and with stirring in Dissolve 100 ml of dimethylformamide and add 5.2 g (0.045 mol) of potassium t-butoxide at 0-10 °. The reaction mixture is stirred for 1 hour at room temperature, then quenched on ice and slowly with 5.1 g (0.015 mol) below 9 ° 6-chloro-2-dichloromethyl-1,2-dihydro-4-phenylquinazoline-3-oxide offset. The reaction mixture is stirred for 17 hours at room temperature.

The reaction mixture is poured onto ice and dichloromethane and made slightly acidic with glacial acetic acid. The watery Phase, is back-extracted three times with dichloromethane. The organic phases are combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to an amber residue. By Crystallization from boiling ethanol gives 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4-oxide as yellow prisms with a melting point of 245-248 (dec.). Addition of an authentic sample did not result in a depression of the melting point.

Example 134

3.37 g (0.03 M) potassium t-butoxide are added to a suspension, cooled to -20 ° and stirred, of 3.5 g (0.01 M) 7-chloro, 3-dihydro-5- (2- fluorophenyl) -2-nitromethylene-2H-1,4-benzodiazepine-4-oxide given in 100 ml of dimethylformamide. After stirring for 10 minutes under nitrogen at this temperature 2.13 g (0.015 M) methyl iodide are added, whereupon stirring is continued for 10 minutes. The reaction mixture is neutralized by adding glacial acetic acid and partitioned between methylene chloride and water. The organic phase is separated dried over sodium sulfate and evaporated. The residue is crystallized from methylene chloride / ethyl acetate and provides 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -3-methy1-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide as yellowish

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Crystals with a melting point of 215-218 °. An analytical sample is recrystallized from the same solvents and has a melting point of 216-218 °.

Example 135

A mixture of 64 mg (0.2 mmol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepine-2-carboxamide and 15 mg (0.4 mmoles) of ethyl aluminum hydride in 3 ml of dry tetrahydrofuran is boiled for 15 minutes. Saturated aqueous sodium sulfate solution is added to the cold reaction mixture. Thin layer chromatographic analysis of the solution obtained shows the presence of starting material as (faster running) Main component and free base 2-aminemethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine as a smaller component.

2 The solution is applied directly to a 20x20 cm preparative thin-layer plate (silica gel), whereupon the plate is developed with ethanol. The lower yellow band is removed and washed twice with methanol / methylene chloride (2: 1) extracted. Evaporation of the filtered extract gives a clear, colorless oil. This is taken up in 1 ml of ethanol, Treated with excess maleic acid (50 mg), scraped and refrigerated overnight. The yellow ones Crystals are collected, washed with ether and air-dried. This product was identified by infrared spectrum in Nujol and due to its melting point of 185-186.5 °, which corresponds to that of an authentic sample (melting point 188 °), as 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -IH-1,4-benzodiazepine dimaleate identified. Of the The mixed melting point was 184-187 °.

Example 136

A mixture of 10 g (0.036 M) 1,3-dihydro-5-phenyl-2H-thieno [3,2-e] [1,4] diazepin-2-one in 50 ml of benzene and 300 ml of tetrahydrofuran is stirred in an ice bath and with methylamine gas saturated. A drop by drop is added to this mixture

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-1

-.157 -

Solution of 9.48 g (0.05 M) titanium tetrachloride in 50 ml benzene admitted. After the addition has ended, the reaction mixture is stirred in an ice bath for 15 minutes. The ice bath will then removed, and the reaction mixture is left for half an hour heated to reflux. The reaction mixture is cooled and 100 g of ice are carefully added. The reaction mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates are combined, dried and evaporated. That Product is crystallized from methylene chloride and gives 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine vom Melting point 223-227 °. Further product with a melting point of 222-225 ° is obtained from the mother liquors. An analytical sample is recrystallized from methylene chloride and has a melting point of 222-229 °.

In a solution, cooled in ice water, of 7.8 g (0.03 M) of 2-methylamino-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine in 100 ml of methylene chloride and 40 ml of pyridine are passed in nitrosyl chloride. The reaction is monitored by thin layer chromatography monitored, the nitrosyl chloride addition is stopped as soon as none Starting material appears more. The reaction mixture is then partitioned between methylene chloride and water. the Methylene chloride solution is dried and evaporated. Obtained by crystallization of the residue from methylene chloride / hexane one 2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] - [1,4] diazepine as yellow crystals with a melting point of 156-159. An analytical sample is crystallized from ether / hexane and shows the melting point 158-160 °.

5.7 g (0.02 M) 2- (N -nitrosomethylamino) -5-phenyl-3H-thieno [3,2-e] [1,4] diazepine are stirred for 10 minutes at room temperature mixture of 15 ml of nitromethane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide are added. After the addition has ended, the reaction mixture is heated on the steam bath under nitrogen and with stirring for 10 minutes. After acidification with 4 ml of glacial acetic acid, the reaction mixture is between methylene chloride / toluene and saturated sodium bicarbonate

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bonat solution distributed. The organic phase is washed with water, dried and evaporated. Crystallization of the residue from methanol with seeding gives 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine as yellow crystals with a melting point of 160-163 °. The seed crystals were obtained by chromatographic purification on a 30-fold amount of silica gel, a 10% solution of Ethyl acetate in methylene chloride was used as the eluent. An analytical sample was recrystallized from methanol and showed melting point 16 3-164.

A solution of 1.42 g (5 mmol) of 1,2-dihydro-2-nitromethylene-5-phenyl-3H-thieno [3,2-e] [1,4] diazepine in 200 ml of ethanol is mixed with 2 teaspoons of Raney -nickel hydrogenated for 1 hour at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. The residue is treated with 1.2 g of maleic acid in 10 ml of 2-propanol. By adding ether, the 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diazepine dimaleate crystallizes as yellow crystals with a melting point of 170-173. An analytical sample was made from methanol / 2 melting point 187-189 ⁽

was recrystallized from methanol / 2-propanol and shows the

,O

1 g (2 mmol) of 2-aminomethyl-2,3-dihydro-5-phenyl-1H-thieno [3,2-e] [1,4] diazepine dimaleate is partitioned between methylene chloride and aqueous ammonia The residue is refluxed with 1 ml of triethyl orthoacetate in 20 ml of xylene for 1 hour. The residue obtained after evaporation of the solvent under reduced pressure is crystallized from 2-propanol / ether and gives 1-methyl-3a, 4- dihydro-6-phenyl-4H-imidazo [l _r 5-a] thieno [2,3-f] [1,4] diazepine with a melting point of 150-152 ° This material is dissolved in 30 ml of toluene with 2 g of activated manganese dioxide during Heated to reflux for 2 hours, the manganese dioxide is filtered off and washed well with methylene chloride, the filtrate is evaporated and the residue is chromatographed on 7 g of silica gel to give a 3% solution

60981 S / 1301

of ethanol in methylene chloride used as the eluent will. The fractions which contain the pure product are combined and evaporated. Through crystallization Methylene chloride / ether and recrystallization from ethyl acetate / hexane give 1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [2,3-f] [1/4 IdIaZePIn from the melting point 223-225 °.

Example 137

A mixture of 7.7 g (0.0278 M) 7-chloro-1,3-dihydro-5-phenyl-2H-thieno [2,3-e] [1,4] diazepin-2-one, 50 ml of benzene and 250 ml of tetrahydrofuran is stirred in an ice bath and with methylamine gas saturated. 7.38 g (0.0389 M) of titanium tetrachloride in 50 ml of benzene are added to this mixture through a dropping funnel. After the addition has ended, the reaction mixture is stirred in an ice bath for 15 minutes. The ice bath is then removed and the reaction mixture is heated to reflux for 20 minutes. The reaction mixture is cooled and carefully added with 100 g Ice cream. The mixture is filtered and the residue is washed with tetrahydrofuran. The filtrates are combined, dried and evaporated. The residue is crystallized from methylene chloride / ether and gives 7-chloro-5-phenyl-2 ~ methylamino ~ 3H ~ thieno [2,3 ~ e] [1,4] diazepine of melting point 246-249 °. An analytical sample is recrystallized from methylene chloride and has a melting point of 247-250 °.

In a solution of 5.8 g (0.02 M) 7-chloro-5-phenyl-2-methylamino-3H-thieno [2,3-e] [1,4] diazepine in 100 ml of methylene chloride and 50 ml of pyridine is added until the reaction has ended (according to the thin layer chromatogram) initiated nitrosyl chloride. The reaction mixture is between water and toluene distributed. The organic phase is dried and evaporated. Obtained by crystallization of the residue from ether / hexane one 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] - [1,4] diazepine as yellow crystals with a melting point of 108-110 °. For analysis purposes, the product is recrystallized from ether / hexane and shows the melting point 111-113 °.

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3.2 g (0.01 M) 7-chloro-2- (N -nitrosomethylamino) -5-phenyl-3H-thieno [2,3-e] [1,4] diazepine become a mixture of 10 ml of nitromethane, 35 ml of dimethylformamide and 2.26 g (0.02 M) Added potassium t-butoxide, which was stirred for 10 minutes under nitrogen at room temperature. After 10 minutes of heating on the steam bath the reaction mixture is added by adding

Acidified 2 ml of glacial acetic acid and then partitioned between water and toluene. The toluene phase is washed with water and dried and evaporated. The residue is crystallized from ethyl acetate / hexane and gives crude 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-e] [1,4] diazepine. This product is purified by chromatography on 40 g of silica gel, whereby a 10% solution of ethyl acetate in methylene chloride is used as the eluent. The pure product is obtained in Form of yellow crystals with a melting point of 154-156.

a) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-d] [1,4] diazepine in 20 ml of ethanol is for 5 hours in the presence of Raney nickel hydrogenated at atmospheric pressure. The catalyst is removed by filtration and the filtrate is evaporated. Of the The residue is chromatographed on 7 g of silica gel, a mixture of methylene chloride, methanol and triethylamine in the 13: 6: 1 ratio is used as the eluant. The pure fractions containing the desired product will be cleaned and evaporated. The residue is treated with maleic acid in 2-propanol. By crystallization of the dimaleate from 2-propanol / ether and recrystallization from ethyl acetate / Ethanol gives 2-aminomethyl 1-7-chloro ^, 3-dihydro-5-phenylH-thieno [2,3-e] [1,4] diazepine dimaleate as yellow crystals with a melting point of 176-177 °.

b) A solution of 320 mg (1 mmol) of 7-chloro-2,3-dihydro-2-nitromethylene-5-phenyl-1H-thieno [2,3-e] [1,4] diazepine in

3 ml of tetrahydrofuran becomes a suspension of 0.8 g of lithium aluminum hydride given in 20 ml of tetrahydrofuran. After refluxing for 5 minutes, the reaction mixture is cooled

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and hydrolyzed by adding 5 ml of water. The inorganic material is removed by filtration and the filtrate is evaporated. The residue is chromatographed as described above, and the pure product is converted into the maleate and yields 2-aminomethyl 1-7-chloro ^, 3-dihydro-5-pheny 1-lH-thieno [2,3-e] [l _/ 4] diazepine dimaleate with a melting point of 176-178 °.

0.52 g (1 mmol) of 2-aminomethyl-7-chloro-2,3-dihydro-5-phenyl-1H-thieno [2,3-e] [1,4] diazepine dimaleate is distributed between methylene chloride and aqueous ammonia. The methylene chloride solution is dried and evaporated.'Der residue is for 1 hour with 0.5 ml of triethyl orthoacetate in 10 ml Xylene heated to reflux. The crude product obtained after evaporation under reduced pressure is dissolved in 25 ml of toluene. After adding 2.5 g of activated manganese dioxide, the solution is refluxed for 11/2 hours. The manganese dioxide is filtered off and the filtrate is evaporated. The residue is chromatographed on 6 g of silica gel, one 4% solution of ethanol in methylene chloride is used as the eluent. The fractions containing the pure product are combined and evaporated. Crystallization of the residue from ether / hexane gives 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine from a melting point of 168-170 °.

Example 138

A solution of 50 g (0.161 M) 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-2H-thieno [2,3-e] [1,4] diazepin-2-one in 900 ml of dry tetrahydrofuran and 300 ml of dry benzene is cooled in an ice bath, saturated with methylamine and with stirring 40 g (0.209 M) titanium tetrachloride in 100 ml benzene were added dropwise. After standing for 4 hours at room temperature a few grams of ice are added and the reaction mixture is filtered. The precipitate is several times with washed hot tetrahydrofuran, and the combined filtrates

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are evaporated. The residue is between 250 ml of dichloromethane and 200 ml of water distributed and filtered. The dichloromethane solution is separated off, dried and evaporated. Of the The residue and the precipitate are recrystallized from a mixture of tetrahydrofuran and ethanol and deliver 7-Chloro-5- (2-chlorophenyl) ~ 2-methylamino-3H-thieno [2,3-e] [1,4] -diazepine. For analytical purposes, a sample is recrystallized from a mixture of tetrahydrofuran and hexane and provides pale yellow prisms with a melting point of 259-262 °.

A mixture of 40 g (0.123 M) 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thieno [2,3-e] [1,4] diazepine, 700 ml of dichloromethane and 350 ml of pyridine are cooled in an ice bath, whereupon nitrosyl chloride is passed in over a period of 20 minutes with stirring will. After 1 hour, nitrosyl chloride is passed in again for 5 minutes, whereupon 600 ml of water are slowly added will. The dichloromethane phase is separated off, washed with 200 ml of water and dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is dissolved in dichloromethane dissolved and filtered through 400 g of Florisil. It is eluted with dichloromethane and then with ether. By crystallization the dichloromethane fraction from a mixture of ether / petroleum ether gives 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H - <- thieno [2,3-e] [1,4] diazepine. Another product is obtained from the ether fraction. A sample is used for analytical Purposes recrystallized from a mixture of ether / petroleum ether and yields yellow prisms with a melting point of 1O4-1O7.

A mixture of 3.4 g (0.03 M) potassium t-butoxide, 7 ml dimethyl malonate and 20 ml dimethylformamide is stirred under nitrogen for 5 minutes. After adding 3.55 g (0.15 M) 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno- [2 _f 3-e] [1,4] diazepine the reaction mixture is heated with stirring for 5 minutes on the steam bath, then acidified by adding 3 ml of acetic acid and crystallized by slowly adding water. The deposited material is collected, washed with water and methanol, and dissolved in methylene chloride

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solved. The methylene chloride solution is dried and evaporated. The residue is crystallized from ethanol and gives 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2 _/ 3-e] [1,4] diazepine as reddish crystals, which are recrystallized from ethanol for analytical purposes and have a melting point of 158-160 °.

A mixture of 2.15 g (5 mmoles) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2,3-e] [1,4] -diazepine , 50 ml of methanol and 0.7 g (1.25 mmol) of potassium hydroxide are refluxed for 3 hours under nitrogen. The solvent is partially removed and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. Crude 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonylmethylene) -2H-thieno [2,3-e] [1,4] -diazepine, which is dissolved in 20 ml of glacial acetic acid, is obtained is resolved. This solution is mixed ₁ .5 g of sodium nitrite with O, for 15 minutes, stirred at room temperature, diluted with water and extracted with methylene chloride. The extracts are washed with water and sodium bicarbonate solution, dried and evaporated. By crystallizing the residue from methylene chloride / ether and recrystallizing from tetrahydrofuran / methanol, 7-chloro-5- (2-chlorophenyl) -a-hydroxyimino-3H-thieno [2,3-e] [1,4] -diazepine- 2-acetic acid methyl ester as yellow crystals with a melting point of 242-245 ° (decomp.).

0.4 g (1 mmol) of 7-chloro-5- (2-chlorophenyl) -a-hydroxyimino-3H-thieno [3,2-f] [1,4] diazepine-2-acetic acid methyl ester is dissolved with heating in 30 ml of tetrahydrofuran and 20 ml of ethanol. Half a teaspoon of Raney nickel is added the reaction mixture is hydrogenated for 45 minutes at atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 10 ml of methanol and treated with 0.4 ml of triethyl orthoacetate and 3 drops of ethanol Treated with hydrochloric acid. After refluxing for 10 minutes the solvent evaporated, and the residue between

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Distributed methylene chloride and sodium bicarbonate solution. The organic phase is dried and evaporated. Man the residue is chromatographed on 10 g of silica gel, using methylene chloride / ethyl acetate (3: 5) as the eluent will. The residue obtained after removing the eluent is crystallized from ethanol and gives 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1, 4] -diazepine-3-carboxylic acid methyl ester of melting point 211-212

Example 139

38 mg (0.001 M) lithium aluminum hydride are added to 20 ml of ether under nitrogen. The reaction mixture is im Cooled the ice bath and add, while stirring, dropwise 0.2 g (0.000493 M) of 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] thieno- [3.2- f] [1,4] diazepine-3-carboxylic acid methyl ester added in 20 ml of dry tetrahydrofuran. After 1 hour, 5 ml of ethyl acetate and then 3 ml of saturated sodium bicarbonate solution are added admitted. The reaction mixture is filtered through celite which is washed with dichloromethane and the combined The filtrates are evaporated. Obtained by crystallization of the residue from a mixture of dichloromethane and ether 8-chloro-6- (2-chlorophenyl) -3-hydroxymethyl-l-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine. By recrystallization the same solvents give whitish prisms with a melting point of 100-110 °, which solidify again and melt at 190-194 °.

Example 140

0.1 g (0.000247 M) are added to 10 ml of methanol and 1 ml of water Methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylate and 0.028 g (0.000493 M) potassium hydroxide. The reaction mixture is heated to reflux for 2 hours and then evaporated. The residue is dissolved in 10 ml of water, washed with 10 ml of ether, acidified with acetic acid and with 30 ml dichloromethane

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extracted. The dichloromethane phase is over anhydrous Dried sodium sulfate, evaporated, cooled and filtered. By recrystallizing the precipitate from a mixture dichloromethane and ether give 8-chloro-6- (2-chlorophenyl) -l-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylic acid as white prisms with a melting point of 242-247.

Example 141

To 0.8 g (0.00204 M) of 8-chloro-6- (2-chlorophenyl) -4H-imida2o- [1,5-a] thieno [3,2-f] [1,4] diazepine-3 -carboxylic acid 0.46 g (0.0022 M) of phosphorus pentachloride are added to 100 ml of dry dichloromethane while cooling with ice. After 30 minutes it will ammonia was passed through the reaction mixture for 5 minutes with stirring. After 2 hours the reaction mixture is with 75 ml of water are added. The deposited product is filtered off, the dichloromethane phase is separated off, dried and evaporated. The product obtained by crystallization of the residue from ethanol becomes with the first precipitate combined and recrystallized from a mixture of chloroform / ethanol, 8-chloro-6- (2-chlorophenyl) -4H-imidazo- [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxamide as white Receives rods with a melting point of 300-305 °.

Example 142

0.125 g (1.1 mmol) of potassium t-butoxide become one on -30 ° cooled solution of 0.325 g (1 mmol) of 8-chloro-6- (2-fluorophenyl) -l-methyl-6H-imidazo [l, 5-a] [1,4] benzodiazepine given in 20 ml of dimethylformamide. After 15 minutes of stirring at -30 to -20, the reaction mixture is by adding Acidified 0.2 ml of glacial acetic acid and then between aqueous sodium bicarbonate solution and methylene chloride / toluene (1: 3) distributed. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on 20 g of silica gel, ethyl acetate being used as the eluent.

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After eluting from starting material, the 8-chloro-6- (2-fluorophenyl) -l-methyl- ^ H-imidazo [1,5-a] [1,4] benzodiazepine becomes collected and crystallized from ether / hexane. Melting point 156-158 °.

Example 143

A solution of 6.8 g (0.0255 M) 6,8-dihydro-3 ~ ethyl-l ™ methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepin-7 (IH) -one in 125 ml of dry tetrahydrofuran and 50 ml of dry benzene is cooled in an ice bath and saturated by passing through methylamine. A solution of 6 _f 3 g (0.0331 M) titanium tetrachloride in 20 ml benzene is then added dropwise with stirring. The reaction mixture is left to stand at room temperature for 18 hours and then cooled to reflux for 30 minutes. The solution is cooled and treated with 4 g of ice * The reaction mixture is filtered and the precipitate is washed with tetrahydrofuran and then with dichloromethane. The combined filtrates are evaporated to dryness, and the residue is crystallized from a mixture of methanol and and recrystallized from a mixture of dichloromethane and ether and gives 3-ethyl-1,6-dihydrO "1-methyl-7-methylamino-4- phenylpyrazolo [3,4-e] [1,4] diazepine as visible prisms with a melting point of 218-221 °.

In a solution of 5.6 g (0.0199 M) 3-ethyl-1,6-dihydrol-methyl-7-methylamino-4-phenylpyrazolo [3,4-e] [1,4] diazepine nitrosyl chloride is passed in 100 ml of dichloromethane and 50 ml of pyridine while cooling in an ice bath and stirring for 10 minutes. After standing for 2 hours at room temperature, nitrosyl chloride is passed in for a further 5 minutes. That The reaction mixture is left to stand for 30 minutes and then poured onto 200 ml of ice. The organic phase is separated, washed with 100 ml of water, dried over anhydrous sodium sulfate and filtered through 100 g of Florisil. That Florisil is washed thoroughly with ether and the combined filtrates are evaporated to dryness. The received

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N-nitroso intermediate is not further purified, but used in the next stage as follows.

A mixture of 14 ml of dimethyl malonate and 35 ml of N, N-dimethylformamide is treated with 6.5 g (0.0580 M) of potassium t-butoxide, whereupon, after stirring for 5 minutes, a solution of the according to N-nitroso compound obtained above in 10 ml of N, N-dimethylformamide is added. The mixture obtained is during Heated for 5 minutes on the steam bath, cooled and mixed with 6 ml of glacial acetic acid. The reaction mixture is cold to 300 ml Poured water, whereupon the solution is decanted after 15 minutes. The oil obtained as a residue is dissolved in 75 ml of dichloromethane solved. The solution is washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and chromatographed through Florisil. The column is first filled with dichloromethane, then with ether and finally with ethyl acetate eluted. The ether and ethyl acetate fractions are combined and evaporated. The residue is made from methanol crystallizes and recrystallizes and gives 3-ethyl-6,8- dihydro-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7 (IH) -ylidene) malonic acid dimethyl ester as whitish rods with a melting point of 145-148 °.

A solution of 1.7 g (0.00445 M) (3-ethyl-6,8-dihydrol-methyl ~ 4-phenylpyrazolo [3,4-e] [1,4] diazepine-7 (IH) -ylidene) -malonic acid dimethyl ester in 40 ml of methanol is treated with 0.56 g (0.01 M) of potassium hydroxide. The solution will be during Heated to reflux for 2.5 hours. The solvent is evaporated and the residue is partitioned between 50 ml of dichloromethane and 30 ml of water distributed. The aqueous layer is first acidified with hydrochloric acid and then basic with ammonium hydroxide and finally extracted with 75 ml of dichloromethane. The organic phases are combined over anhydrous Dried sodium sulfate and filtered through Florisil. The Florisil is eluted first with ether and then with ethyl acetate. The eluates are combined and evaporated to give crude monoester as OeI. This product is no longer cleaned

609815/1301

but dissolved in 10 ml of glacial acetic acid and with stirring with 0.35 g (0.005 M) sodium nitrite treated. After 45 minutes, the reaction mixture is poured onto 100 ml of water and mixed with 75 ml of dichloromethane extracted. The organic phase is washed with 50 ml of dilute sodium bicarbonate solution, over anhydrous Dried sodium sulfate and evaporated to dryness. The residue is made from a mixture of ethyl acetate and ether crystallized. Recrystallization from a mixture of dichloromethane and ether gives 3-ethyl-1,6-dihydro-hydroxyimino-1-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7-acetic acid methyl ester as whitish rods with a melting point of 225-227 °.

A solution of 0.35 g (0.000986 M) 3-ethyl-l, 6-dihydroa-hydroxyimino-l-methyl-4-phenylpyrazolo [3,4-e] [1,4] diazepine-7-acetic acid methyl ester in 20 ml of dry tetrahydrofuran and 25 ml of methanol is mixed with 2 ml (0.0109 M) of triethyl orthoacetate and a Raney nickel spatula. The reaction mixture is for 2.5 hours at room temperature and Hydrogenated at atmospheric pressure. The catalyst is removed by filtration and washed with methanol. The combined filtrates are evaporated and the residue is dissolved in 50 ml of dichloromethane. The solution is diluted with 40 ml of ammonium hydroxide washed, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is in a solution of 50 ml of methanol containing 2 ml (0.109 M) of triethyl orthoacetate and 0.2 ml (0.00114 M) of 5.7N ethanolic hydrochloric acid, while Heated to reflux for 20 minutes. The solvents are evaporated under reduced pressure. The residue is in Dissolved dichloromethane, and the solution is washed with dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated. The crude product obtained as OeI is on 3 silica gel thick-layer plates with a mixture of 5% methanol developed in ethyl acetate. The Rf 0.5 product is scraped off, stirred with methanol and filtered. the Solution is evaporated and the residue is crystallized from ether. 3-Ethyl-1,6-dihydro-1,9-dimethyl-

609815/1301

methyl carboxylate as white prisms with melting point ,O

4-phenyl-imidazo [1,5-a] pyrazolo [4,3-f] [1,4] diazepine-7-carbonsc

181-184 ^C

Example 144

A mixture of 3.3 g (0.01 M) 7-chloro ~ 1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine-4-oxide, 3.3 ml of phosphorus trichloride and 300 ml of methylene chloride are stirred for 4 hours at room temperature. The solution is with 10% washed aqueous sodium carbonate solution, dried over sodium sulfate and evaporated. The crude product is at 100 g Chromatographed silica gel, a 10% solution of ethyl acetate in methylene chloride is used as the eluent. The combined clear fractions are made from methylene chloride / Hexane crystallizes and gives 7-chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4-benzodiazepine as light yellow crystals with a melting point of 184-186 °.

Example 145

A mixture of 3.6 g (0.01 M) 7-bromo-2- (N-nitrosomethylamino) -5- (2-pyridyl) -3H-1,4-benzodiazepine, 30 ml dimethylformamide, 5 ml nitromethane and 2 g (0.018 M) potassium t-butoxide is stirred for 15 minutes at room temperature and then slowly warmed. When the temperature has reached 100 °, will the reaction mixture is cooled and neutralized by adding glacial acetic acid. That after the addition of saturated aqueous sodium bicarbonate solution precipitated product is collected, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. By crystallization of the residue from methylene chloride / ethanol 7-bromo-1,3-dihydro-2-nitromethylene-5- (2-pyridyl) -2H-1,4-benzodiazepine is obtained as a light yellow product with a melting point of 232-235 ° (decomp.). For analytical purposes the product is taken out Tetrahydrofuran / ethanol recrystallizes and has a melting point of 240-245 ° (decomp.).

6 0 9 8 15/1301

Example 146

A mixture of 31 g (0.075 M) 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide, 4 g (0.095 M) sodium hydroxide, 300 ml methanol and 5 ml water is refluxed for 3 hours. After cooling, the reaction mixture is diluted with water. The eliminated Crystals are collected and recrystallized from methanol and yield 7-chloro-1,3-dihydro-2- (methoxycarbonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide with a melting point of 215-216 °.

1.4 g (0.02 M) sodium nitrite become a solution of 6.8 g (0.02 M) 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide put in 100 ml of glacial acetic acid. After stirring for 15 minutes at room temperature, the Reaction mixture diluted with 100 ml of water. The eliminated Crystals are collected, washed with water and dried and yield 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzo ~ diazepine-2-acetic acid methyl ester as a yellow product from Melting point 237-239 (dec.). An analytical sample is recrystallized from dimethylformamide / methanol and shows the same Melting point.

Example 147

A solution of 1 g (0.00358 M) of 7-cyano-2,3-dihydro-5- (2-fluorophenyl) -lH-l, 4-benzodiazepin-2 ~ is one in the presence of 0 _r 5 teaspoons of Raney Nickel hydrogenated for 5 hours and then left to stand for 18 hours without stirring. The reaction mixture is filtered through Celite and concentrated to a small volume. A solution of 0.9 g (0.004 M) picric acid in 10 ml of ethanol is added. The precipitated salt is filtered and crystallized twice from a mixture of tetrahydrofuran and methanol and gives 7-aminomethyl-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one picrate as yellow Prisms with a melting point of 194-198.

6 0 9 8 15/1301

25A0522

Example 148

A solution of 2.8 g (0.00932 M) DL-2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophenyl) -1H-1,4-benzodiazepine in 40 ml of dichloromethane is mixed with 2.5 g (0.0119 M) of trifluoroacetic anhydride treated. After 5 minutes, the reaction mixture is washed with 15 ml of 10% potassium carbonate solution, over dried anhydrous sodium sulfate and evaporated to dryness. The residue is crystallized from dichloromethane and recrystallized from a mixture of dichloromethane and hexane to give 7-chloro-2,3-dihydro-5- (2-fluorophenyl) -2-trifluoroacetaminomethyl-lH-1,4-benzodiazepine as pale yellow prisms with a melting point of 140-143.

Example 149

To a solution of 10 g (0.0264 M) 5- (2-fluorophenyD-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-2-one 1.8 g (0.039 M) of 54% sodium hydride are added in 140 ml of dry tetrahydrofuran with stirring and under nitrogen. The reaction mixture is heated to reflux for 1 hour, cooled to 0 ° and treated with 10.8 g (0.0422 M) phosphorodimorpholine chloride. After 18 hours the solution is filtered, evaporated to a small volume and mixed with ether. Of the Solid is filtered off and recrystallized from a mixture of dichloromethane and ether and gives 5- (2-fluorophenyl) -7-iodo-2- [bis- (morpholino) phosphinyloxy] -3H-1,4-benzodiazepine as white platelets with a melting point of 104-112 °.

A solution of 27 g (0.443 M) nitromethane in 450 ml of dry dimethyl sulfoxide is cooled to 0 ° and below Stir and add 5.4 g (0.119 M) 54% sodium hydride under argon. The reaction mixture is 2 hours at room temperature left to stand and then cooled to 0 ° and treated with 39.5 g (0.06 M) 5- (2-fluorophenyl) -7-JOd ^ -EbIs- (morpholino) phosphinyloxyl-SH-1,4-benzodiazepine offset. The reaction mixture is stirred for 18 hours at room temperature and then on

60981S / 1301

Poured 3 liters of ice and water containing 15 ml of acetic acid. The precipitated solid is filtered off and dissolved in 700 ml of dichloromethane. The solution is washed with 300 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is crystallized from a mixture of dichloromethane and ether and recrystallized and provides 2,3-dihydro-5- (2-fluorophenyl) -7-iodo-2-nitromethylene-1H-1,4-benzodiazepine as yellow prisms with a melting point of 214-216 °.

Example 150

A stirred suspension of 3.35 g (0.075 M) of a 54% dispersion of sodium hydride in mineral oil in 267 ml Dimethylformamide is mixed with 17.5 g (0.08 M) diethylacetamidomalonate in several portions under argon. The reaction mixture is for a further 30 minutes at room temperature stirred and then in one portion with 26.7 g (0.05 M) 7-bromo-2- [bis (morpholino) phosphinyloxy] -5- (2-pyridyl) -3H-1,4-benzodiazepine offset. The reaction mixture is stirred under argon for a further 7 hours at room temperature. That The dark mixture is poured onto ice / acetic acid and diluted with water to give a green-yellow solid. The solid is filtered off, washed with water and air-dried. Approximately 7 g of this solid are deposited on silica gel chromatographed, using ethyl acetate as the eluant, and yield an amorphous solid, which shows a spot of Rf 0.5 on thin layer chromatography (ethyl acetate). If the solid with a small proportion Isopropanol is stirred, crystallization occurs. Obtained by recrystallization of a sample from isopropanol one acetylamino [7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepin-2-yl] malonic acid diethyl ester as light brown platelets with a melting point of 178-180 °.

6 0 9 8 15/1301

example

0.46 g (2.2 mmol) of phosphorus pentachloride are added to a suspension of 0.785 g (2 mmol) of 8-chloro-6- (2- chlorophenyl) -lmethyl-4H-imidazo [1,5-a] thieno [3 , 2-f ] [l, 4] diazepine-3-carboxylic acid in 50 ml of methylene chloride. After stirring for 30 minutes Nitrogen in an ice bath is passed in until the dimethylamine mixture has an alkaline reaction Minutes at room temperature, washing with saturated sodium bicarbonate solution, dries and evaporates. Crystallization of the residue from ethyl acetate / ether gives 8-chloro-6- (2-chlorophenyl) -l, H, lT-trimethyl-4H-imidazo [l, 5-a] -thieno [3,2-f] [l, 4] diazepine-3-carboxamide in the form of whitish crystals, which are recrystallized from ethyl acetate for analysis purposes "and then melt at 197-200 °.

Example 152

A solution of 4.15 g (20.1 mmol) of 2 - [(phenylmethylene) amino] ethyl acetate * N-oxide in 200 ml of tetrahydrofuran is cooled to -73 ° and then slowly added dropwise mixed with 13.2 ml (21.2 mmol) of n-butyl lithium in hexane, a faint orange solution is formed. After 15 minutes, a solution of 10.15 g (20 mmol) is slowly added dropwise 7-chloro-2 ~ [bis (morpholino) phosphinyloxy] -5- (2-fluorophenyl) -3H-1,4-benzodiazepine in 225 ml of tetrahydrofuran, the resulting dark brown suspension can be allowed to rise to room temperature heat and stir overnight. The mixture is with 3 nil Water decomposes and the solvent is removed in vacuo. The residue is diluted with 300 ml v / ater and repeated several times extracted with ether. The combined organic phases ■ are washed twice with water and once with saline solution, dried over anhydrous magnesium sulfate and concentrated in vacuo, taking the crude product in the form of a light yellow

609815/1301

Solid obtained. Recrystallization from aqueous acetone gives 8-chloro-6- (2-fluorophenyl) -l-pheny1-4H-imidazo [l, 5-a] [l, 4] T3enzodiazepine-3-carboxylic acid ethyl ester in the form of a white crystalline solid. When constricting a further portion of the end product is obtained from the mother liquor.

* E. Buehler and G-.B. Brown, J. Org. Chem., 32, 265 (1967).

Example 153

A parenteral use form is produced according to the following composition:

Per ml

8-chloro-l-methyl-5- (2-fluorophenyl) -

4H-imidazo [1,5-a] [1,4] benzodiazepine

maleate 1.0 mg

Benzyl alcohol 0.15 ml

Containing tartaric acid buffer
Sodium hydroxide

Water for injections q.s. ad 1 ml

In a glass container or a container coated with glass, 8 liters of water for injections are grounded heated to 90 °. After cooling to 50-60 °, 1.5 liters of benzyl alcohol are used added with stirring. The solution is then brought to room temperature. Under a nitrogen atmosphere and 10 g of 8-chloro-1-methy1-6- (2-fluorophenyl) -4H-imidazo [1,5-a] are stirred [l, 4] benzodiazepine maleate added. The pH is adjusted to 3.0 + 1.0, preferably 3.0 + 0.5, with a combination of tartaric acid buffer and sodium hydroxide solution. The solution is brought to the final volume of 10 1 with water for injections. The solution is through a Filtered candle filters and filled into suitable ampoules, which are sealed with nitrogen gas.

60.9815 / 1301

Example 154

In the following way, tablets of the following composition are made:

Per tablet

8-chloro-6- (2-fluorophenyl) -1-methyl-

4H-imidazo [I, 5-a] [1,4] benzodiazepine

maleate "10.0 mg

Lactose 113.5 mg

Corn starch 70.5 mg

Pregelatinized corn starch 8.0 mg

Calcium stearate 3.0 mg

Total weight 205.0 mg

.8-chloro-6- (2-fluorophenyl) -1-methy1-4H-imidazo [1,5-a] ti, 4] benzodiazepine maleate is mixed with the lactose, corn starch and pregelatinized corn starch in a suitable mixer. The mixture is passed through a grinding machine. The mixture is returned to the mixer and moistened with water to form a thick paste. The wet mass is returned to the shredder and at 45 ° dried. The dry granulate is returned to the mixer, the calcium stearate is added and mixed well. The granules are compressed into tablets of 200 mg.

609815/1301

Example 155

In the following way, tablets of the following composition are made:

Per tablet

8-chloro-6- (2-fluorophenyl) -1-methyl-

4h-imidazo [1,5-a] [1,4] benzodiazepine

maleate 25.00 mg

Lactose 64.50 mg

Corn starch 10.00 mg

Magnesium stearate 0.50 mg

Total weight 100.00 mg

The 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [l, 5-a] · [1,4] Benzodiazepine maleate is mixed in a suitable mixer mixed with the lactose, corn starch and magnesium stearate. The mixture is passed through a grinding machine. The mixed powder is made on a tablet press machine pressed into lumps. The lumps are crushed to a suitable size and mixed well. On that you press tablets weighing 100 mg.

609815/1301

Example 156 Capsules of the following composition are produced:

Per capsule

8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4-benzodiazepine maleate

Lactose corn starch talc

Total weight 225 mg

The 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is mixed with the lactose and corn starch in a suitable mixer. the Mixture is then passed through a grinder. The mixed powder is placed in the mixer brought back, added the talc and mixed well again. The mixture obtained is poured on a capsule filling machine filled in hard gelatine capsules.

25th mg 158 mg 37 mg 5 mg

60981B / 1301

Example 157 Capsules of the following composition are prepared:

4H-imidazo [1,5-a] [1,4 ^ maleate

Lactose corn starch talc

Per capsule -l-methyl- ZiULiJ-CLZrCipXIl 50 mg 125 mg 30th mg 5 mg total weight 210 mg

The 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [l, 5 ~ a] · [1,4] Benzodiazepine maleate is mixed in a suitable mixing device mixed with the lactose and corn starch. The mixture is then passed through a grinding machine. The mixed powder is returned to the mixing device, the talc is added and mixed well again. The mixture obtained is filled into hard gelatin capsules on a capsule filling machine.

609815/1301

Example 158 Capsules of the following composition are produced:

Per capsule

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate

Lactose corn starch talc

Total weight 210 mg

The 8-chloro-1,4-dimethyl-6 ~ (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate is mixed with the lactose and corn starch in a suitable mixer « The mixture is then passed through a grinding machine. The mixed powder is placed in the mixer brought back, added the talc and mixed well again. The mixture obtained is filled into hard gelatine capsules on a capsule filling machine.

50 mg 125 mg 30th mg 5 mg

60981B / 1301

-180- · ■

Example 159 Capsules of the following composition are produced:

8-Chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine maleate

Lactose corn starch talc

Total weight 225 mg

The 8-chloro-1,4-dimethyl-6 ~ (2-fluorophenyl) -4H-imidazo- [1,5-a] tl, 4] benzodiazepine maleate is mixed with the lactose and corn starch in a suitable mixer, The mixture is then passed through a grinding machine. The mixed powder is placed in the mixer brought back, added the talc and mixed well again. The mixture obtained is poured on a capsule filling machine filled in hard gelatine capsules.

Per capsule mg 25th mg 158 mg 37 mg 5

609815/1301

Example 160

In the following manner, tablets become the following Composition made:

Per tablet

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -

4H-imidazo [1,5-a] [I, 4] benzodiazepine

maleate 25.00 mg

Lactose 64.50 mg

Corn starch 10.00 mg

Magnesium stearate 0.50 mg

Total weight 100.00 mg

The 8-chloro-l _/ 4-dimethyl-6- (2-fluorophenyl) -4H-imidazo- [1,5-a] [1,4] benzodiazepine maleate is combined with the lactose, the corn starch and the magnesium stearate in one suitable mixer mixed. The mixture is passed through a grinding machine. The mixed powder is compressed into lumps on a tablet machine. The lumps are crushed to a suitable size and mixed well. Tablets weighing 100 mg are pressed.

■ 809815/1301

Example 161

In the following way, tablets of the following composition are made:

Per tablet

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -

4H-imidazo [1,5-a] [1,4] benzodiazepine

maleate 10.0 mg

Lactose 113.5 mg

Corn starch 70.5 mg

Pre-gelatinized corn starch 8.0 mg

Calcium stearate 3.0 mg

Total weight 205.0 mg

8-chloro-1,4-dimethyl-6- (2-fluorophenyl) -4H-imidazo [1,5-aJ [1,4] benzodiazepine maleate is mixed with the lactose, corn starch and pregelatinized in a suitable mixer Corn starch mixed. The mixture is passed through a grinding machine. The mixture is in the Mixer brought back and moistened with water to form a thick paste. The wet mass is through a crusher passed, and the moist granules are at 45 dried. The dry granulate is returned to the mixer, the calcium stearate is added and mixed well. The granules are compressed into tablets with a total weight of 200 mg.

6 0 9 8 15/1301

Example 162

A parenteral use form is made accordingly the present composition:

Per ml

e-chloro-l ^ -dimethyl-o- (2-fluorophenyl) -

4H-imidazo [1,5-a] [1.43 benzodiazepine

maleate I ₇ O mg

Benzyl alcohol 0.15 ml

Containing tartaric acid buffer
Sodium hydroxide

Water for injections q.s. ad 1 ml

8 liters of water for injections are placed in a glass container or a container coated with glass heated to 90 °. After cooling to 50-60 °, 1.5 liters of benzyl alcohol are used added with stirring. The solution is then brought to room temperature. Under a nitrogen atmosphere and 10 g of e-chloro-l ^ -dimethyl-o- (2-fluorophenyl) -4H-imidazo [l, 5-a] [l, 4] benzodiazepine maleate are stirred admitted. The pH is adjusted with a combination of tartaric acid buffer and sodium hydroxide solution set to 3.0 + 1.0, preferably 3.0 + 0.5. The solution is brought to the final volume of 10 1 with water for injections. The solution is through a Filtered candle filters and filled into suitable ampoules, which are sealed with nitrogen gas.

609815/1301

Claims (2)

Claims ! JL. Process for the preparation of imidazo [1,5-a] [1,4] diazepine compounds the general formula where A is the G group -C = IT, R-, hydrogen, lower alkyl ', lower hydroxyalkyl, lower acyloxyalkyl, phenyl, lower alkoxyalkyl, lower haloalkyl, lower aminoalkyl, substituted lower aminoalkyl, substituted phenyl, pyridyl, aralkyl or the groups RCO or ROOC- (where R is hydrogen or lower alkyl), Rp Hydrogen, lower alkyl, lower hydroxyalkyl, 'lower' acyloxyalkyl, lower alkoxyalkyl, lower alkenyl, lower haloalkyl, lower aminoalkyl, amino, cyano, lower cyanoalkyl, substituted amino, substituted lower aminoalkyl, the group ROOC- (where R is hydrogen or lower Alkyl), the group RCO (where R is hydrogen or lower alkyl), or derivatives thereof, ie the group RC = Ii-R '(where R ^{1 is} hydrogen, lower alkyl, hydroxy, phenyl, alkoxy, amino, mono- or Dialkylamino or arylamino and R is hydrogen or lower 609815/1301 Are alkyl), the group -COFt (where R " and R ¹ "are each hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl or aryl or R ^{1 r} and R ¹ " together form part of a heterocyclic ring or the group (CHg) _n NR R (where R and R are hydrogen , lower alkyl, lower hydroxyalkyl, lower alkenyl or aryl or R and R together form part of a heterocyclic ring) or the group ¹⁰ 11 (where R ¹⁰ , R ¹¹ and R ¹² Hydrogen, lower alkyl or the group (CH ₉ ) n 1 "to 4 and ^ R whereby ■ yz ΊΑ ^{ά ά} ^ and R hydrogen or lower T * 2 T A res are alkyl or R and R together form part of a heterocyclic ring) means R ~ and Rp- Wass only off, lower alkyl, lower alkanoyloxy, Hydroxy or lower alkoxycarbonyl mean, where for the Pail that one of R ^ and Rr-Alkanoy loxy, hydroxy or lower. Is alkoxycarbonyl, the other is hydrogen or is lower alkyl, R. is hydrogen, halogen, kitro, cyano, trifluonaethyl, lower alkyl, means substituted amino, amino, lower hydroxyalkyl or lower alkanoyl, R ^ Phenyl, mono-substituted phenyl, di-substituted • fcuierter Phenyl, pyridyl or mono-substituted Pyridyl means and one of the groups and 60981B / 1301 means, where X is chlorine, bromine or iodine and T is hydrogen or lower alkyl, of analogous compounds which of the formula I but correspond to where A is the group H ι y -C-IT is 'R- and R' together an additional -I \ 3 3 lent ö / E bond form, R, R _? > (Z | and R _ß have the meaning given in formula I and Rf denotes hydrogen or lower alkyl or in which A is one of the groupings \ ■ and ■ IV R _v RO S- - ö means, R- ,, Rp, Rg and (z | i those in formula I have given meaning, R "hydrogen, means lower alkyl, lower alkenyl, lower alkynyl, acyl, hydroxy, nitroso, an aromatic or aliphatic or lower alkoxycarbonyl, R ^ and R ₁ - mean hydrogen or lower alkyl and Y is hydrogen or lower alkyl , ' and of pharmaceutically acceptable acid addition salts of these Compounds which, in the case of certain compounds of the formula I, have a structure in which the diazepine ring is cleaved the C / N double bond is opened in the 5,6 position, thereby marked that one aa) for the preparation of a compound of the formula 609815/1301 where A -G = is, IL, R ₉ , R, - and IB in the and Formula I have given meaning and ^ Rp- hydrogen or lower alkyl mean a Compound of formula I converted into its ΪΓ-oxide, or ab) a compound of the formula IB, wherein A is -C = N- ^ T, A ° and the Be given in formula I Have meaning and one of R- and R ^ is hydrogen and the other is hydrogen or lower alkyl, converted by methods known _{per se into a compound of the formula I in which R ~ or R 1} - is alkanoyloxy, or ac) a compound of the formula I in which R ~ or R _{1 is} alkanoyloxy is converted by methods known per se into a corresponding compound of the formula I in which R or R _{1 is} hydroxy, or ad) for the preparation of a compound of the formula 15/1301 -χσα- wherein IB ^! those in formula I. , R ^, R ^ jy "| j" j- ¹ "· - ^ Have the meaning given and R. has the meaning given in formula I but is not nitro and R, - has the meaning given in formula I. but is not nitrophenyl, a corresponding compound of the formula I is reduced or ae) for the preparation of a compound of the formula IB, wherein H A -QW ^ , where R _{7 is} ¹ lower alkyl, lower R ₆ ^X R ^ Alkenyl, lower alkynyl, acyl, hydroxy, nitroso, an aromatic or aliphatic sulfonyl group or is lower alkoxycarbonyl, for example a corresponding compound of the formula IB ' with a lower alkyl halide (e.g. methyl iodide), a lower alkenyl halide (e.g. allyl bromide), a lower alkynyl halide (e.g. propargyl bromide), an alkyl or aryl sulfonyl halide (e.g. tosyl chloride, Mesyl chloride), nitrosyl chloride or a a lower alkanoyl group supplying agent (e.g. acetyl chloride) or af) a compound of the formula IB, in which A -C = N "^", A ° to a corresponding compound of the formula IB, wherein 609815/1301 A -y-HC ^ is reduced or OH * H ag) a compound of the formula IB, wherein A -C-I B OH ^R 6 is dehydrated to the corresponding compound of the formula I, or H I ah) a compound of the formula IB, wherein A —C-Ης ^ " R ₆ is, where R ₇ ^{1 is} acetyl, mesyl or tosyl, converted into a corresponding compound of the formula I or H ai) a compound of the formula IB, wherein A is -G-HH, converted into a corresponding compound of the formula I by oxidation of the secondary amine in the 5-position, or a 3) a compound of the formula. ■ R ₁ - wherein R, hydrogen, lower alkyl, lower Hydroxyalkyl, lower acyloxyalkyl, phenyl, lower alkoxyalkyl, lower haloalkyl, lower aminoalkyl, substituted lower aminoalkyl, substituted phenyl, pyridyl, $ 098 15/1301 lower aminoalkyl, substituted lower aminoalkyl, substituted phenyl, pyridyl, aralkyl or the groups RCO or ROOO- (where R. is hydrogen or lower alkyl) ", R ₂ denotes hydrogen, lower alkyl, lower hydroxyalkyl, lower acyloxyalkyl, lower alkoxyalkyl , lower alkenyl, lower haloalkyl, lower aminoalkyl, cyano, lower cyanoalkyl, substituted amino, substituted lower.aminoalkyl, the group ROOC- (where R is hydrogen or lower alkyl), the group RCO (where R is hydrogen or lower alkyl), the group -CON C ^ (where R ¹ ' and E ¹ "are each hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl or aryl, or R ^1? and R ¹ " together are part of a hetero- TV V form cyclic ring or the group (CE ₂ ) JSR-; ^a (where R ¹ ^ and R hydrogen, lower alkyl., rJLe.de- IV V res are alkenyl, or aryl, or R and R together form part of a heterocyclic ring) or the ■ group -. . -.- ■ -. ^ R ¹¹ j_ ^^ inn 19 -COMTCT -T ₉ (where R, R and R are lower alkyl "- * R or the group (CH ^) ₉ ER ¹⁵ R ¹⁴ where η 1 to 4 and R ¹⁵ and R are lower alkyl or R and R together form part of a heterocyclic ring) is Rf- is hydrogen or lower alkyl, R. is hydrogen , Halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, or lower alkanoyl and Rg denotes phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl, to a corresponding compound of iOrmel I. , cyclized ^ vein 6033 15 / for the preparation of a compound of formula IB wherein A is where V is hydrogen or lower -G-H Alkyl means a corresponding compound of the formula I in the presence of a Lewis acid Ethylene oxide or propylene oxide or a corresponding compound of the formula * ι ^ -γ ^N V XXIV with ethanolamine, a 1-alkylethanolamine or a 2-Alky3Ethanolamine converts, or a ketal group present as R. in an imidazobenzodiazepine in the corresponding etone substituents convicted, or one present as R. in an imidazobenzodiazepine Ketone group converted into a secondary or tertiary alcohol group, or a compound of the formula VII 609815/1301 wherein A is -C = N, Rp, R "and R ₁ - hydrogen or mean lower alkyl and R ₁ , (Zn, R. and R ^ A. \ _l ^^ 4 ο have the meaning given in formula I, where but R. not nitro and R, - not substi-4 by nitro ο is tuiert, dehydrated to a corresponding compound of the formula I, or for the preparation of a compound of the formula IA where A -C-N, R ^, and Rr those in formula I have the meaning given and R ^ is hydrogen or lower alkyl, the double bond in the 5,6-position of a corresponding compound of the formula I isomerized in the 4,5-position, or ao) a compound of formula I wherein R. acylamino, subjects' mild hydrolysis, while a _r ent speaking compound of formula I is ,, wherein R. is amino, or a compound of the formula 6098 15/1301 VII ¹ HI wherein A -C-I is, and E-,, E ₂ , E., || and Eg that given in Formula VII Have meaning, oxidized to a corresponding compound of the formula I, or a compound of the formula XVII wherein E is lower alkyl, by reaction with a suitable acylating agent directly in a corresponding compound of the formula I is converted, or a compound of the formula 609815/1301 CDOR XX wherein B. is lower alkyl, oxidized to a corresponding compound of the formula I, or as) a compound of the formula XIX wherein R is lower alkyl, by. Dehydration and simultaneous cyclization in one corresponding compound of formula I converted or at) a compound of the formula COOR XVIII 609815/1301 wherein R is lower alkyl, to the corresponding hydrolyzed free acid, or au) a compound of the formula XVIII to the corresponding compound of the formula -CH CB XXIII reduced, or a compound of the formula XXIII to a corresponding compound of the formula XXIV wherein R is lower alkyl, acylated, or aw) a compound of the formula XXIII to a corresponding compound of the formula XXV oxidized, or ax) the hydroxyl group in the 3-position substituent of a Compound of the formula XXIII replaced by halogen, or ay) the halogen in the 3-position substituent in one Compound of formula wherein.X is halogen, nucleophilic by a another nucleophilic group, such as an amine, alkoxide or cyanide, replaced, or az) the aldehyde group in the ^ position of a compound of the formula XXV with a lower alkyl or aryl . .. "Grignard, .Or, - ^ LithlumreagenZ ,: brings about, reaction, ... or . ■ ba) subjecting a compound of the formula XVIII to ammonolysis with ammonia or a primary amine, or bb) an "acid chloride ", a compound .., of the formula XKII 6 09 a 1.57-1301 with a primary or secondary amine or with ammonia, or bc) for the preparation of a compound of the formula XXXII dehydrated a corresponding COHEp compound, or bd) subjects a compound of the formula XVIII to direct hydrazinolysis, or be) an acid chloride of a compound of the formula XXII with a hydrazine converts, or bf) a compound of the formula XXII is deearboxylated, or bg) a compound of the formula XXXIII heated with an alcohol, or 609815/1301 bh) a compound of the formula NHCOOR XXX V wherein R is benzyl, converted into the corresponding free amine, or bi) a compound of the formula acylated with an acid halide or acid anhydride, or b; j) a compound of the formula XXJLVl with a strong JBase and an alkoxycarbonyl chloride converts to form a "compound of the formula 6098 15/1301 XXXVIII or bk) a compound of the formula COOR alkylated in the 4-position, or ^; bl) a compound of the formula XVXEI i-HQH κ χ Connection de ^ 'Förii ^ l \ _ oju:?;:.: XXX oxidized, or bm) a compound of the formula XL or XXV is treated with a hydrazine of the formula HH ₂ UR ¹ R "(in which R 'and R" are hydrogen, lower alkyl or aryl), with hydroxylamine or with alkoxyamines, or bn) a compound of the formula XLII to a corresponding compound of the formula XLIII reduced, or
bo) a compound of the formula XXXVI halogenated in 3-position, or 609815/1301 "bp) a compound of the Pormel "where A -0-Ή or -C =. XLV is and R _n lower Alkyl "means into a corresponding compound of the formula XLVI "where R is hydrogen or lower alkyl and A is the meaning given in formula XLV owns, convicts ouer bc [) a compound of the formula XLVI into a corresponding one Connection of the formula XLVIII 609S15 / 1301 in which A and R have the meaning given in formula XLVI, or br) a compound of the formula XLVIII to give a corresponding compound of the formula XLVII wherein A and R have the meaning given in formula XLVI own, oxidized, or bs) a compound of the formula NO treated with alcohol, or bt) a compound of the formula HCOOR LII 8 1 5 / 130-1 "where Ε _{Λ is} not nitro-substituted. to a corresponding compound of the formula LI reduced, or bu) a compound of the formula ■ where R is lower alkoxy or KR ¹ R "(where R 'and R" are lower alkyl) and R-,' phenyl, substituted phenyl or pyridyl, dehydrated to a corresponding compound of the formula I, or bv) a racemic compound in its optischeii S separates, or bw) a compound of the formula I or an analogous V ^ -M'- ⁵ ^ ¹ S * which corresponds to the formula: but corresponds to wherein A is the group -C-U "', R" "and R' together R ₆ V ₅ ". Form an additional C / F bond, 6098 1S / TaOf- ν-: and Rg has the meaning given in formula I "and R ₁ - is hydrogen or lower alkyl, or where A is one of the groupings. \ and "means, R ^ _t R ^, R _g and \ Ζ [Γ have the meaning given in formula I, R ₁₇ hydrogen, lower alkyl, lower alkenyl, lower alkynyl, acyl, hydroxy, nitroso, an aromatic - ■ matisehe or aliphatic (sulfonyl) group -. '* or lower alkoxycarbonyl, R " _r and" Rj-- denotes hydrogen or, lower, alkyl be; - ". : ■ - ■ -. . . ':. interpreter-n. and T: V / a hydrogen or-lower alkyl; .- is, '■ - ■■; ■ ..' converted into a pharmaceutically usable acid addition salt ". 2. The method according to claim 1, characterized in that daös ''" one ·.; Ye "2? bond. ■ of the formula I, in which ■ (E | ^r [· .. ■ - .. ■ the grouping [■ '■' ibt, A ^j -C = N, R ₁ 'hydrogen or lower Alkyl denotes, R ₅ denotes hydrogen or lower alkyl, R ^ 'and Rj- denote hydrogen, lower alkyl, "lower alkanoyloxy, or hydroxyl /' where for the case, 'that one of''' R ~ and Rf- alkanoyloxy or Hydroxy, the other hydrogen or lower alkyl is ^ RV 'hydrogen, hemiogen,' nitro, 'cyano, trifluoromethyl, lower alkyl ; amino, iilower hydroxyalkyl or lower alkanoyl and R> phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or möriö-substi- 6098 15/1301. tuierte pyridyl means analogous compounds which but correspond to formula I in which A is -C-N \, R ^ R ₆ R ' ₅ and R 'together form an additional C / N bond and R ₁ - is hydrogen or lower alkyl, or in which A the group -C-IT or -C = IT, R ^ and R ₁ - hydrogen R ₆ R ₇ R ₆ O or lower alkyl and R _{7 is} hydrogen, lower alkyl, lower alkenyl, lower alkynyl, acyl, hydroxy, an aromatic or aliphatic sulfonyl group or lower alkoxycarbonyl, or pharmaceutically acceptable acid addition salts thereof are prepared, and that procedure aa), ab), ac ), ad), ae), an), ao), bv) and bw) of claim 1. 3. The method according to claim 1, characterized in that a compound of the formula I is prepared in which R ₁ Is hydrogen or lower alkyl, \ Z \\ the G group is, R is hydrogen, nitro or halogen, R 1 is phenyl, or phenyl substituted by halogen, nitro or lower alkyl, R _{2 is} hydrogen, lower alkyl, lower hydroxyalkyl, a carboxylic acid hydrazide group or an oarboxamide group and R 1 and R 1 are hydrogen. 4. The method according to claim 2 or 3, characterized in that R _{2 is} hydrogen or lower alkyl. 5. The method according to claim 4 »characterized in that R _{1 is} lower alkyl and R _{2 is} hydrogen. 6. The method according to any one of claims 3 Isis 5 »characterized in that R _{4 is} halogen in the 8-position and R _{2 is} 2-halophenyl 609815/1301 mean. 7. The method corresponding to that which is claimed in any one of claims 2 to 6, characterized in that R ₁ - mean lower alkyl. 8. The method according to claim 7, characterized in that Ep- is methyl. 9. The method according to claim 6, characterized in that 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] -benzodiazepine manufactures. 10. The method according to claim 8, characterized in that 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-iirn.dazo- [l, 5-a] [l, 4] benzodiazepine manufactures. 11. The method according to claim 5 »characterized in that 8-chloro-6- (2-fluorophenyl) -3-hydroxymethy 1-1-methy 1-4H-imidazo [1,5-a] £ 1,4] benzodiazepine manufactures. 12. The method according to claim 3> characterized in that that 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [l, 5-a] - [l, 4] benzodiazepine-3-carboxylic acid hydrazide manufactures. 13. The method according to claim 5 »characterized in that that 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [l, 5-a] - [l, 4] benzodiazepine-5-carboxamide manufactures. 14. The method according to claim 1, characterized in that that one can use 8-chloro-O- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxamide manufactures. 15. The method according to claim 1, characterized in that 8-chloro-6- (2-cElorphenyl) -l, H ", M" -trimethyl-4H-imidazo- 6098 15/1 3D 1 [l, 5- * a] thieno [3 »2-f] [l, 4] diazepine-3-carboxamide. 16. The method according to claim 1, characterized in that 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, llH-imidazo [1,5-a] oxazolo [3,2-d] [1,4] "benzodiazepine, 17. The method according to claim 1, characterized in that that 7-ethyl-l, 9-dimethyl-6-phenyl-4H, 9H-imidazo [l, 5-a] -pyrazolo [4,3-f] [l, 4] diazepine-3-carboxylic acid methyl ester manufactures. V: C 6098tS- / t3QT 18. Process for the manufacture of preparations with
Muscle-relaxing, sedative and anticonvulsant properties, characterized in that a compound of the formula I defined in claim 1, an analogous compound thereof as defined in claim 1, or a pharmaceutically acceptable acid addition salt of such a compound as an active ingredient with non-toxic, inert , therapeutically acceptable solid or liquid carriers and / or excipients commonly used in such preparations. 609815/1361 19 »Preparations with muscle-relaxing, sedative and anticonvulsant properties, containing a compound of the formula I defined in claim 1, a compound analogous to it as defined in claim 1, or
a pharmaceutically acceptable acid addition salt of such a compound and a carrier. £ 09815/1301 - 2IO - 20. Imidazo [l, 5-a] [l, 4] diazepine compounds of the general formula where A is the G group -C = IT, R-, hydrogen, lower alkyl, lower hydroxyalkyl, lower acyloxyalkyl, phenyl, lower alkoxyalkyl, lower haloalkyl, lower aminoalkyl, substituted lower aminoalkyl, substituted phenyl, pyridyl, aralkyl or the groups RCO or ROOC- (where R is hydrogen or lower Alkyl is) means, Rp is hydrogen, lower alkyl, lower hydroxyalkyl, lower "acyloxyalkyl, lower alkoxyalkyl, lower alkenyl, lower haloalkyl, lower aminoalkyl, amino, cyano, lower gyanoalkyl, substituted amino, substituted lower aminoalkyl, the group RQOC- (wherein R is hydrogen or lower alkyl), the G group RCO (where R is hydrogen or lower alkyl), or derivatives thereof, ie the group RC = IT-R ¹ '(where R' is hydrogen, lower alkyl, hydroxy, phenyl , "Alkoxy, amino, mono- or dialkylamino or arylamines and R is hydrogen or lower Are alkyl), the group -COlT-Q (where. R " and R ^{t11 are} each hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl, or aryl 60.98 15/130 or R ¹ 'and R ^{1 f} together part of a hetero- IY Y form cyclic ring or the group (CH _p ) HR R (where R ¹ ^ and R ^{V are} hydrogen, lower alkyl, lower hydroxyalkyl, lower alkenyl, or aryl IV Y or R and R assume part of a heterocyclic one Ring "form) or the group R ¹¹
₁₂ (where R, R and R ^{x are} hydrogen, 1 * 5 14-lower alkyl or the group (CH ₂ ) ₂ NR ^J R where n 1 "to 4 and B." and R are hydrogen or lower alkyl or. R 'and R ^ together form part of a heterocyclic ring ") means, R ~ and R ₁ - mean hydrogen, lower alkyl, lower alkanoyloxy, hydroxy or lower alkoxy carbonyl, where for the Pail that one of R, and R ₁ - is alkanoyloxy, hydroxy or lower.Alkqxycarbonyl, the other is hydrogen or lower alkyl, R / hydrogen, halogen, nitro, cyano, trifluoromethyl-lower alkyl, substituted,; amino, ..amino , lower hydroxyalkyl or -me.deres .... Alksnoyl means Rg _v phenyl, mono-substituted · ^ s Bhenyl, -di-substi-- tuiertes -phenyl ,. pyridyl, _or: iiiono-substitutability tes ^: Pyridyl means · - 'and st. IUJ one of the groups "means, where X'CB-lor, bromine or iodine and 0? Are hydrogen "or" lower_ alkyl, 6 0 9 8.1 5 · / .1 3 D -V - ^; ' ^: K' original! NSPECTED analogous compounds which correspond to the formula I but in which A is the group ΐ / -GN is 'R- and R' together. An additional E ₆ V ₃ Form C / N bond, B ₁ , R ₉ , föli and R, - have the meaning given in formula I and R ₁ -hydrogen or lower. Alkyl or where A is one of the groupings H C- • N. -and ^R 6. Rg and those in formula I. "means, R- ,, R have given meaning, R "hydrogen, lower alkyl, lower alkenyl, lower alkynyl, acyl," hydroxy * nitroso, an aromatic or aliphatic ^ sulfonyl group or lower alkoxycarbonyl means, R ~ · .. -.-... and Rj- Hydrogen or lower alkyl mean and.V hydrogen or lower alkyl ■ let, · ' - ■■ - "■■■■■■ ■; ■'. "-.. ■■: · ■■ ^ - ■ - - .,"; ..- ·. · ', .- ■■■■ ·., -. :. ... and pharmaceutically usable acid addition salts of these compounds which, in the case of certain compounds of the formula I, have a structure in which the diazepine ring is opened by cleavage of the C / N double bond in the 5,6 position. , 21. Compounds according to claim 20 of the formula I in which the group R / is, 60981571301 ■ r 213 - A is -C = U, R, hydrogen or lower Alkyl denotes, Rp denotes hydrogen or lower alkyl, E, and R ₁ - denotes hydrogen, lower alkyl, lower alkanoyloxy or hydroxy, where for the Pail that one of alkanoyloxy or hydroxy is the other Is hydrogen or lower alkyl, R. is hydrogen, halogen, nitro, cyano, trifluoromethyl, is lower alkyl, amino, lower hydroxyalkyl or lower alkanoyl and Rg is phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl or mono-substituted pyridyl means, analogous compounds which correspond to formula I but H
ι wherein A is -G-Νζ ^ , R, and R'- together an additional Form σ / Κ bond and R ₁ - hydrogen or lower alkyl means, or wherein A is -UN ^- S. or -C = Ir, R. * and R ^ ■ ^fi 6 ⁸ TR ₆ O Denotes hydrogen or lower alkyl and R ₇ denotes hydrogen, lower alkyl, lower alkenyl, lower alkynyl, acyl, hydroxy, an aromatic or aliphatic sulfony group or lower alkoxycarbonyl, and pharmaceutically acceptable acid addition salts of these compounds. Compounds according to claim 2O of the formula I, in which denotes hydrogen or lower alkyl, fejj die Group R. ~ k Jl is ,. R. Hydrogen, ffitro or halogen "means Rg phenyl or by halogen, ITitro or lower Alkyl is substituted phenyl, Rp is hydrogen, lower ■ 609815/1301 res denotes alkyl, lower hydrocyclic alkyl, a carboxylic acid hydrazide group or carboxamido "and R" and R _n - are hydrogen. 23. Compounds according to claim 21 or 22, wherein is hydrogen or lower alkyl. 24 '. Compounds according to claim 2.3 ', in which R _{1 is} lower alkyl and Rp is hydrogen » 25 :. Compounds according to any one of claims 22 to 24, wherein R.sup.8 is halogen and R.sup.2 is 2-halophenyl. 26th Compounds according to those recited in any one of claims 22 ^; up to = 2.5, in which, however, R ₁ . means lower alkyl. 27 Compounds according to claim 2 / ir, in which R _{1 is} - .Methyl. 23 S-chloro-6- (2-fluorophenyl) -l-methyl ^ H -imidazo {1,5-a] [1,4] benzodiazepines 29t '. 8-chloro-6- (2-fluorophenyl) -1,4-dimethyl-4H-imidazo [ 1,5-? A] [1,4] b enzodiaz epin. 3Q /. S-chloro-ö- ^ 2-fluorophenyl) -3-hydroxymethyl-1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 31. 8-ChIOr-S- (2-fluorophenyl) -l-methyl ^ H-imidaz 0, 4] benzodiazepine-3-carboxylic acid hydrazide. . 8-Chloro-6- (2-fluorophenyl) -l-methyl ^ H -imidazo- [1,5-a] - [1,4] benzodiazepine-3-carboxamide. ■ SV 9 8 1 5/1 3 0 1 33. 8-Chloro-6- (2-chloroph.enyl) -l-methyl ^ H -imidazo- [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxamide. 34. 8-Clilor-6- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5 ~ a] thieno [3,2-f] [1,4] diazepine-3-carboxamide. 3.5. 2-chloro-13a- (2-fluorophenyl) -12,13a-dihydro-6-methyl-9H, lIH-imidazo [1,5-a] oxazolo [3,2-f] [1,4] benzodiazepine. 36. 7-Ethyl-l, 9-dimethyl-6-phenyl-4H, -9H-imidazo [1,5-a] pyrazolo- [4,3-f] [l> 4] diazepine-3-carboxylic acid methyl ester. 609815/1301